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1
Hammami, Muhammad M., Abderrezak Bouchama, Essam Shail, Hassan Y. Aboul-Enein, and Sultan Al-Sedairy. "Lymphocyte subsets and adhesion molecules expression in heatstroke and heat stress." Journal of Applied Physiology 84, no. 5 (May 1, 1998): 1615–21. http://dx.doi.org/10.1152/jappl.1998.84.5.1615.
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We examined the specificity of the recently reported alterations in circulating lymphocytes in heatstroke by determining lymphocyte subsets in 14 consecutive heatstroke patients before and after cooling and in 7 heat-stressed controls using single- or two-color immunofluorescence flow cytometry. The relationship with catecholamine levels was also studied. In heatstroke, percentages of T (CD3+/CD19−), T-helper (CD4+/CD8−), T-inactive [CD3+/human leukocyte antigen-DR−], CD11a+, CD11c+, and CD44+lymphocytes were significantly decreased, whereas percentages of T-suppressor-cytotoxic (CD8+/CD4−), natural killer (NK; CD3−/CD16+or CD56+), CD3+/CD16+or CD56+, and CD54+lymphocytes were significantly increased, compared with 11 normal controls. The changes in the absolute numbers of lymphocyte subsets were in the same direction and were significant for T-helper, T-suppressor-cytotoxic, NK, CD3+/CD16+or CD56+, and CD11c+lymphocytes. Milder but significant changes in percentages of T-helper, T-suppressor-cytotoxic, CD11c+, and CD44+lymphocytes were seen in heat stress. Cooling was associated with partial or complete normalization, further derangement (CD11a+, CD11c+), or overcorrection (NK, T-suppressor-cytotoxic, CD11b+) of abnormal percentages of lymphocyte subsets. Norepinephrine levels were significantly elevated in heatstroke (4.7-fold) and heat stress (3.2-fold), but did not significantly correlate with lymphocyte subsets. We conclude that heatstroke is associated with significant changes in percentages and in absolute numbers of a wide range of circulating lymphocyte subsets that are not related to elevated catecholamine levels or totally normalized by cooling. Similar, albeit milder, changes are seen in heat stress, suggesting that the two syndromes represent a continuum.
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Plachynta, M. "CD4+ T-helpers in TCR-dependent tumor immunosurveillance and T-cell based adoptive transfer immunotherapy: are they really that helpful?" Cell and Organ Transplantology 3, no. 1 (May 31, 2015): 87–91. http://dx.doi.org/10.22494/cot.v3i1.20.
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In this brief review the advances and hurdles of the modern-day ACT (adoptive cell transfer) immunotherapy of cancer are discussed, with the focus on the positive or negative role of CD4+ T helper lymphocytes as one of major constituents of oncologic patient-administered CIK (cytokine-induced killers) lymphocyte culture. The beneficial role of CD4+ T helpers in adoptively-transferred lymphocyte culture is considered, questioned and being put under doubt. “Infectious tolerance” and tumor “immune avoidance” phenomena are described, emphasizing on their dramatic implications for cancer ACT therapy. The ways to circumvent apparent undesired effects of CD4+ T helpers elevated presence in CIK bulk mass are discussed, such as complete removal of CD4 -positive cells, along with a less radical measure, which is depletion of CD4+CD25+FoxP3+ T regulatory lymphocytes from bulk CIK culture.
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Moon, Joon Ho, Jin Ho Baek, Dong Hwan Kim, Sang Kyun Sohn, Jong Gwang Kim, Kyu Bo Lee, and Jang Soo Suh. "Rapid Helper T-Cell Recovery at 3 Months Correlates to Successful Transplant Outcomes after Allogeneic Stem Cell Transplantation." Blood 106, no. 11 (November 16, 2005): 5201. http://dx.doi.org/10.1182/blood.v106.11.5201.5201.
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Abstract Background: The current study attempted to evaluate the role of a simple quantitative measurement of peripheral lymphocyte subsets, especially CD4+ helper T-cell recovery, in predicting transplant outcomes, including overall survival (OS), non-relapse mortality (NRM), and opportunistic infections, after allogeneic stem cell transplantation (SCT). Methods: A total of 69 patients receiving an allogeneic SCT were included. The disease entities were as follows: AML 42, ALL 5, CML 15, NHL 5, and high-risk MDS 2. The peripheral lymphocyte subset counts, such as CD3+ T-cells, CD3+4+ helper T-cells, CD3+8+ cytotoxic T-cells, CD19+ B-cells, and CD56+ natural killer (NK) cells, were measured 3, 6, and 12 months post-transplant. Results: The CD19+ B-cell reconstitution was slow, while a rapid CD56+ NK cell recovery was noted. The CD4+ helper T-cell reconstitution at 3 months was strongly correlated with OS (p<0.0001), NRM (p=0.0007), and opportunistic infections (p=0.0108) when stratifying patients with cut-off value of 200×106/L CD4+ helper T-cells. A rapid CD4+ helper T-cell recovery was also independently associated with a higher CD4+ helper T-cell transplant dose (p=0.006) and donor type (p<0.001) in a regression analysis. An early CD4+ helper T-cell recovery at 3 months was associated with a subsequent faster helper T-cell recovery until 12 months, yet not with B-cell recovery. In a multivariate survival analysis, a combination of a higher CD34+ cell dose and rapid recovery of CD4+ helper T-cells at 3 months was found to a have favorable prognosis in terms of OS (p=0.001, hazard ratio [HR] 3.653) and NRM (p=0.005, HR 4.836), yet not relapse. Conclusion: A rapid recovery of the CD4+ helper T-cell count above 200×106/L at 3 months seemed to correlate with a faster immune reconstitution and predict a successful transplant outcome. Figure. The overall survival according to the helper T-cell counts at 3 months (A) and the difference of total T-(B) and helper T-cell (C) immune reconstitution within 1-year post-transplant according to helper T-cell counts at 3 months Figure. The overall survival according to the helper T-cell counts at 3 months (A) and the difference of total T-(B) and helper T-cell (C) immune reconstitution within 1-year post-transplant according to helper T-cell counts at 3 months
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Harcourt, Gillian C., Sarah Garrard, Miles P. Davenport, Anne Edwards, and Rodney E. Phillips. "HIV-1 Variation Diminishes CD4 T Lymphocyte Recognition." Journal of Experimental Medicine 188, no. 10 (November 16, 1998): 1785–93. http://dx.doi.org/10.1084/jem.188.10.1785.
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Effective long-term antiviral immunity requires specific cytotoxic T lymphocytes and CD4+ T lymphocyte help. Failure of these helper responses can be a principle cause of viral persistence. We sought evidence that variation in HIV-1 CD4+ T helper epitopes might contribute to this phenomenon. To determine this, we assayed fresh peripheral blood mononuclear cells from 43 asymptomatic HIV-1+ patients for proliferative responses to HIV-1 antigens. 12 (28%) showed a positive response, and we went on to map dominant epitopes in two individuals, to p24 Gag restricted by human histocompatibility leukocyte antigen (HLA)-DR1 and to p17 Gag restricted by HLA-DRB52c. Nine naturally occurring variants of the p24 Gag epitope were found in the proviral DNA of the individual in whom this response was detected. All variants bound to HLA-DR1, but three of these peptides failed to stimulate a CD4+ T lymphocyte line which recognized the index sequence. Antigenic variation was also detected in the p17 Gag epitope; a dominant viral variant present in the patient was well recognized by a specific CD4+ T lymphocyte line, whereas several natural mutants were not. Importantly, variants detected at both epitopes also failed to stimulate fresh uncultured cells while index peptide stimulated successfully. These results demonstrate that variant antigens arise in HIV-1+ patients which fail to stimulate the T cell antigen receptor of HLA class II–restricted lymphocytes, although the peptide epitopes are capable of being presented on the cell surface. In HIV-1 infection, naturally occurring HLA class II–restricted altered peptide ligands that fail to stimulate the circulating T lymphocyte repertoire may curtail helper responses at sites where variant viruses predominate.
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Losurdo, Giuseppe, Domenico Piscitelli, Federica Pezzuto, Francesco Fortarezza, Claudia Covelli, Antonella Marra, Andrea Iannone, et al. "T Helper Lymphocyte and Mast Cell Immunohistochemical Pattern in Nonceliac Gluten Sensitivity." Gastroenterology Research and Practice 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/5023680.
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Background and Aims. Nonceliac gluten sensitivity (NCGS) is a gluten-related emerging condition. Since few data about NCGS histopathology is available, we assessed the markers of lymphocyte and innate immunity activation. Materials and Methods. We retrieved duodenal biopsy samples of patients with NCGS diagnosis according to the Salerno criteria. We selected specimens of positive (seropositive celiac disease/Marsh 1-2 stage) and negative (normal microscopic picture) controls. Immunohistochemistry for CD3 (intraepithelial lymphocytes-IELs), CD4 (T helper lymphocytes), CD8 (T cytotoxic lymphocytes), and CD1a/CD117 (Langerhans/mast cells) was performed. ANOVA plus Bonferroni’s tests were used for statistical analysis. Results. Twenty NCGS, 16 celiac disease, and 16 negative controls were selected. CD3 in NCGS were higher than negative controls and lower than celiac disease (18.5 ± 6.4, 11.9 ± 2.8, and 40.8 ± 8.1 IELs/100 enterocytes; p<0.001). CD4 were lower in NCGS than controls and celiac disease (31.0 ± 22.1, 72.5 ± 29.5, and 103.7 ± 15.7 cells/mm2; p<0.001). CD8 in NCGS were similar to negative controls, but lower than celiac disease (14.0 ± 7.4 and 34.0 ± 7.1 IELs/100 enterocytes, p<0.001). CD117 were higher in NCGS than celiac disease and negative controls (145.8 ± 49.9, 121.3 ± 13.1, and 113.5 ± 23.4 cells/mm2; p=0.009). Conclusions. The combination of CD4 and CD117, as well as IEL characterization, may be useful to support a clinical diagnosis of NCGS.
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Semple, JW, and J. Freedman. "Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia." Blood 78, no. 10 (November 15, 1991): 2619–25. http://dx.doi.org/10.1182/blood.v78.10.2619.2619.
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Abstract Chronic autoimmune thrombocytopenic purpura (ATP) is a common hematologic disorder in which platelet-specific autoantibodies bind to platelets and enhance their destruction by the reticuloendothelial system. While there has been considerable investigation of the humoral immune abnormalities in ATP, little work has been performed on the cellular immunoregulatory aspects of this autoimmune disorder. We describe here that patients with ATP have lymphocytes that proliferate normally when stimulated by mitogens. However, when stimulated by normal control platelets in 7-day antigen-presenting cell cultures, peripheral blood mononuclear cells (PBMC) from patients with ATP proliferate at significantly higher levels (P less than .001) and their lymphocytes secrete significantly higher amounts of interleukin-2 (IL- 2) (P less than .001) than do lymphocytes from control subjects. Depletion studies with monoclonal anti-CD8 and complement did not reduce the proliferative capacity of the responding PBMC population, indicating that CD4+ T-helper cells may be responsible for the response. Phenotypic analysis of peripheral blood lymphocyte subsets from patients with ATP showed that there was a significant reduction in CD4+Leu8+ T suppressor-inducer cells (P less than .001) and a concomitant increase in CD3+DR+ activated T cells (P less than .001) and CD19+ B cells (P less than .05). These data indicate that CD4+ T- helper cells from patients with ATP are stimulated by normal platelet antigen(s) to secrete IL-2 and may modulate the enhanced antiplatelet autoantibody response.
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Semple, JW, and J. Freedman. "Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia." Blood 78, no. 10 (November 15, 1991): 2619–25. http://dx.doi.org/10.1182/blood.v78.10.2619.bloodjournal78102619.
Full textAbstract:
Chronic autoimmune thrombocytopenic purpura (ATP) is a common hematologic disorder in which platelet-specific autoantibodies bind to platelets and enhance their destruction by the reticuloendothelial system. While there has been considerable investigation of the humoral immune abnormalities in ATP, little work has been performed on the cellular immunoregulatory aspects of this autoimmune disorder. We describe here that patients with ATP have lymphocytes that proliferate normally when stimulated by mitogens. However, when stimulated by normal control platelets in 7-day antigen-presenting cell cultures, peripheral blood mononuclear cells (PBMC) from patients with ATP proliferate at significantly higher levels (P less than .001) and their lymphocytes secrete significantly higher amounts of interleukin-2 (IL- 2) (P less than .001) than do lymphocytes from control subjects. Depletion studies with monoclonal anti-CD8 and complement did not reduce the proliferative capacity of the responding PBMC population, indicating that CD4+ T-helper cells may be responsible for the response. Phenotypic analysis of peripheral blood lymphocyte subsets from patients with ATP showed that there was a significant reduction in CD4+Leu8+ T suppressor-inducer cells (P less than .001) and a concomitant increase in CD3+DR+ activated T cells (P less than .001) and CD19+ B cells (P less than .05). These data indicate that CD4+ T- helper cells from patients with ATP are stimulated by normal platelet antigen(s) to secrete IL-2 and may modulate the enhanced antiplatelet autoantibody response.
8
Goseva, Zlatica, Biserka Jovkovska Kaeva, Angelko Gjorcev, Elena Jovanovska Janeva, Zoran Arsovski, Sava Pejkovska, and Aleksandra Tatabitovska. "Analysis of Lymphocyte Immunological Reactivity in Patients with Pleural Effusions of Different Etiology." Open Access Macedonian Journal of Medical Sciences 4, no. 1 (December 25, 2015): 50–53. http://dx.doi.org/10.3889/oamjms.2016.009.
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BACKGROUND: The proportion of T and B lymphocytes in pleural fluids and blood may point to the presence of local immunological phenomena in pleural disorders.AIM: Aim of study was to evaluate the lymphocyte phenotype and the ratio between helper (CD4+) and cytotoxic/suppressor (CD8+) lymphocytes in malignant and non-malignant effusions.MATERIAL AND METHODS: We studied 48 patients with pleural effusions. First group had 18 patients with tuberculosis pleural effusions; second group had 20 patients with malignant pleural fluids, third group had 10 patients with transudates and 30 healthy controls. We investigated the distribution of T and B lymphocytes, T cells with helper/inducer CD4 or suppresser/cytotoxic CD8 phenotypes and the CD16 subset.RESULTS: Results showed decreases levels of CD3, CD4, and CD16 T cells in blood of patients versus healthy controls. There were increases in the percentage of the CD3 and CD4 T cells in the pleural fluid compared with values in the blood with statistical significance in tuberculous pleurisy. The values of CD8 were similar in the pleural fluid and in blood. Levels of CD16 were non-significantly higher in pleural fluid in all groups.CONCLUSION: This study confirms the hypothesis that pleural cavity is compartment with immunological reactivity and results could be used in differential diagnosis together with other examinations.
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Choong, M. L., S. H. Ton, and S. K. Cheong. "Influence of Race, Age and Sex on the Lymphocyte Subsets in Peripheral Blood of Healthy Malaysian Adults." Annals of Clinical Biochemistry: International Journal of Laboratory Medicine 32, no. 6 (November 1995): 532–39. http://dx.doi.org/10.1177/000456329503200603.
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The lymphocyte subsets in the peripheral blood of healthy Malaysian adults (212 subjects, age 18–71 years) were analysed using a flow cytometer FACScan in an effort to establish a reference range for the lymphocyte subsets. The lymphocyte subsets studied were T cells (CD3), B cells (CD19), natural killer (NK) cells (CD3−CD16+/CD56+), helper/inducer cells (CD4), cytotoxic/suppressor cells (CD8) and the helper/suppressor ratio (CD4/CD8). The distributions of T cells, CD4 cells and CD8 cells were symmetric about their means while B cells, NK cells and CD4/CD8 ratio followed a skewed distribution. Differences in race were observed for T cells, NK cells, CD4 cells and CD4/CD8 ratio where the Indians were significantly different from the Malays and the Chinese (higher T cells, CD4 cells and CD4/CD8 ratio and lower NK cells). The B cells were significantly lower in the Chinese than the Malays and the Indians. Age differences were seen only in the Chinese where increased CD4 cells and CD4/CD8 ratio, and decreased CD8 cells were observed. A sex difference was observed only in the Chinese where the CD4/CD8 ratio was significantly higher in females than males.
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Mearns, Helen, William G. C. Horsnell, J. Claire Hoving, Benjamin Dewals, Antony J. Cutler, Frank Kirstein, Elmarie Myburgh, Berenice Arendse, and Frank Brombacher. "Interleukin-4-Promoted T Helper 2 Responses Enhance Nippostrongylus brasiliensis-Induced Pulmonary Pathology." Infection and Immunity 76, no. 12 (September 22, 2008): 5535–42. http://dx.doi.org/10.1128/iai.00210-08.
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ABSTRACT The role of CD4+ T-cell interleukin-4 (IL-4) receptor alpha (IL-4Rα) expression in T helper 2 (TH2) immune responses has not been defined. To examine this role, we infected CD4+ T-cell IL-4Rα knockout (KO) mice with the parasitic nematode Nippostrongylus brasiliensis, which induces strong host TH2 responses. Although N. brasiliensis expulsion was not affected in CD4+ T-cell IL-4Rα KO mice, the associated lung pathology was reduced. Infected CD4+ T-cell IL-4Rα KO mice showed abrogation of airway mucus production. Furthermore, CD4+ T-cell IL-4Rα KO mouse lungs contained reduced numbers of lymphocytes and eosinophils. Restimulation of pulmonary region-associated T-cell populations showed that TH2 cytokine responses were disrupted. Secretion of IL-4, but not secretion of IL-13 or IL-5, from mediastinal lymph node CD4+ T cells was reduced in infected CD4+ T-cell IL-4Rα KO mice. Restimulation of tissue-derived CD4+ T cells resulted in equivalent levels of IL-4 and IL-13 on day 7 postinfection (p.i.) in control and CD4+ T-cell IL-4Rα KO mice. By day 10 p.i. the TH2 cytokine levels had significantly declined in CD4+ T-cell IL-4Rα KO mice. Restimulation with N. brasiliensis antigen of total lung cell populations and populations with CD4+ T cells depleted showed that CD4+ T cells were a key TH2 cytokine source. These data demonstrated that CD4+ T-cell IL-4 responsiveness facilitates eosinophil and lymphocyte recruitment, lymphocyte localization, and TH2 cytokine production in the allergic pathology associated with N. brasiliensis infections.
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Weimer, R., T. Schweighoffer, K. Schimpf, and G. Opelz. "Helper and suppressor T-cell function in HIV-infected hemophilia patients." Blood 74, no. 1 (July 1, 1989): 298–302. http://dx.doi.org/10.1182/blood.v74.1.298.298.
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Abstract T-lymphocyte helper and suppressor functions were assessed in 61 hemophilia patients. Twenty one patients were HIV-negative (Group 1), 27 were HIV-positive without having AIDS-related complex (ARC)/AIDS (Group 2), and 13 had ARC/AIDS (Group 3). T, CD4-positive, or CD8- positive T lymphocytes were cocultured with B lymphocytes and pokeweed mitogen for 6 days and immunoglobulin producing cells were assessed in a reverse hemolytic plaque assay. In HIV-infected patients, T cells as well as the CD4-positive T cell subset exhibited reduced helper (P less than .01, Group 2; P less than .0005, Group 3) and elevated suppressor activity (P less than .02, Group 2; P less than .005, Group 3), whereas no significant difference was found between HIV-negative patients and controls. The number of CD4-positive cells was not correlated with CD4 cell function. CD4-positive cells showed no helper activity (less than 10% of control T cells) in 8/11 (73%), but an excessive suppressor activity (greater than 80% suppression of plaque formation) in 6/11 (55%) Group 3 patients. Our results show that defective helper and elevated suppressor functions of T cells in HIV-infected patients are caused not only by a change in the CD4/CD8 cell counts but also by functional abnormalities of the CD4-positive T-cell subset. These abnormal helper and suppressor functions may play a role in the development of the immunodeficiency state of AIDS patients.
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Weimer, R., T. Schweighoffer, K. Schimpf, and G. Opelz. "Helper and suppressor T-cell function in HIV-infected hemophilia patients." Blood 74, no. 1 (July 1, 1989): 298–302. http://dx.doi.org/10.1182/blood.v74.1.298.bloodjournal741298.
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T-lymphocyte helper and suppressor functions were assessed in 61 hemophilia patients. Twenty one patients were HIV-negative (Group 1), 27 were HIV-positive without having AIDS-related complex (ARC)/AIDS (Group 2), and 13 had ARC/AIDS (Group 3). T, CD4-positive, or CD8- positive T lymphocytes were cocultured with B lymphocytes and pokeweed mitogen for 6 days and immunoglobulin producing cells were assessed in a reverse hemolytic plaque assay. In HIV-infected patients, T cells as well as the CD4-positive T cell subset exhibited reduced helper (P less than .01, Group 2; P less than .0005, Group 3) and elevated suppressor activity (P less than .02, Group 2; P less than .005, Group 3), whereas no significant difference was found between HIV-negative patients and controls. The number of CD4-positive cells was not correlated with CD4 cell function. CD4-positive cells showed no helper activity (less than 10% of control T cells) in 8/11 (73%), but an excessive suppressor activity (greater than 80% suppression of plaque formation) in 6/11 (55%) Group 3 patients. Our results show that defective helper and elevated suppressor functions of T cells in HIV-infected patients are caused not only by a change in the CD4/CD8 cell counts but also by functional abnormalities of the CD4-positive T-cell subset. These abnormal helper and suppressor functions may play a role in the development of the immunodeficiency state of AIDS patients.
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Saakyan, Svetlana Vladimirovna, Natalya Vladimirovna Balatskaya, Ludmila Anatolievna Katargina, Irina Gennadievna Kulikova, and Elena Borisovna Myakoshina. "SUBPOPULATION COMPOSITION OF PERIPHERAL BLOOD LYMPHOCYTES IN UVEAL MELANOMA." Medical Immunology (Russia) 21, no. 4 (October 29, 2019): 765–72. http://dx.doi.org/10.15789/1563-0625-2019-4-765-772.
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Uveal melanoma is a malignant neuroectodermal tumor. Despite of radical primary treatment with the use of enucleation of the eye or radiation therapy, almost in 50% of patients develop metastatic disease. The effectiveness of various methods of treatment of malignant tumors, the prognosis of the disease largely depend on the state of the patient's immune system. Data on the ratio of lymphocytes of different populations, their relationship with the stages of uveal melanoma are currently not available. 84 patients with uveal melanoma were examined (44 women and 40 men; mean age 53.7 ± 12.2 years). In group 1 (small tumors) included 36 patients, in the 2nd (medium-sized tumors) - 26 patients, 22 patients made up the 3rd group (large tumors). The control group included 33 practically healthy donors. The material of the study was samples of whole blood taken from the ulnar vein on an empty stomach in the morning with the help of vacuum systems in test tubes Vacuette® with anticoagulant K3EDTA. Immunophenotyping was performed using flow laser cytofluorimetry using the Multitest 6-Color TBNK Reagent monoclonal antibody system in BD TruСount test tubes (Becton Dickinson, USA), BD FACSCanto II cytometer (Becton Dickinson, USA). Erythrocyte lysis and leukocyte fixation were performed using a BD FACS ™ Lysing Solution lysing solution (Becton Dickinson, USA). The relative and absolute levels of lymphocyte populations and subpopulations were determined in the Canto program (Becton Dickinson, USA), with the selection of the analyzed region in the general population expressing CD45 + antigen and cell granularity (CD45 + PerCP-Cy5,5 * / SSC); fluorochromes labeled antibodies to CD3 + (FITC), CD4 + (PE-Cy7 *), CD8 + (APC-CY7 *), CD16 + / 56 + (PE), CD19 + (APC *) were used to differentiate: T-lymphocytes (CD3 +), T-helper cells (CD3 + CD4 + CD8-), T-cytotoxic (CD3 + CD4-CD8 +), T-double positive (CD3 + CD4 + CD8 +), NK-cells (CD16 + CD56 +), B-lymphocytes (CD19 +) , calculate the ratio of CD3 + CD4 + / CD3 + CD8 + subpopulations - the index reflecting the balance of T-helper cells and cytotoxic T-cells (CD4 + / CD8 +). Our individual analysis of the composition of lymphocytes allows us to conclude that the growth of uveal melanoma is accompanied by systemic multidirectional changes in the qualitative and quantitative composition of immunocompetent cells, affecting both innate (NK cells) and adaptive (T-lymphocytes) links of antitumor immune defense. The results are important for the development of personalized approaches to the prognosis and treatment of patients with uveal melanoma. The dynamics of changes in the quantitative composition of lymphocyte subpopulations in oncological diseases may be of value for monitoring immunotherapeutic effects and supplement the clinical assessment of the course of the underlying disease.
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Forster, R., T. Emrich, E. Kremmer, and M. Lipp. "Expression of the G-protein--coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells." Blood 84, no. 3 (August 1, 1994): 830–40. http://dx.doi.org/10.1182/blood.v84.3.830.bloodjournal843830.
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The G-protein-coupled receptor BLR1 related to receptors for chemokines and neuropeptides has been identified as the first lymphocyte-specific member of the gene family characterized by seven transmembrane-spanning regions. Using a high-affinity anti-BLR1 monoclonal antibody (MoAb) and three-color flow cytometry it is shown that BLR1 expression on peripheral blood cells is limited to B cells and to a subset of CD4+ (14%) and CD8+ (2%) lymphocytes. T cells expressing BLR1 were positive for CD45R0, were negative for interleukin-2 receptors, show high levels of CD44, and show low levels of L-selectin. The majority of CD4+ cells originating from secondary lymphatic tissue, but none of cord blood- derived T cells, express BLR1. These observations suggest that BLR1 is a marker for memory T cells. Furthermore, BLR1 expression was detected on all CD19+ peripheral or tonsillar B lymphocytes, but only on a fraction of cord blood cells and bone marrow cells expressing CD19, sIgM, or sIgD. Interestingly, activation of both mature B and T cells by CD40 MoAb and CD3 MoAb, respectively, led to complete downregulation of BLR1. These data suggest that the G-protein-coupled receptor BLR1 is involved in functional control of mature recirculating B cells and T- helper memory cells participating in cell migration and cell activation.
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Kovacikova, Lubica, Veronika Krasnanova, Peter Skrak, Martin Zahorec, Andrea Kantorova, Jana Semberova, and Ljuba Bacharova. "Immune Abnormalities in Patients With Single Ventricle Circulation Precede the Fontan Procedure." World Journal for Pediatric and Congenital Heart Surgery 8, no. 6 (November 2017): 672–82. http://dx.doi.org/10.1177/2150135117732529.
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Background: Immune abnormalities are common in Fontan patients with protein-losing enteropathy. Limited data exist on immune function of other patients with single ventricle circulation. Methods: This prospective cohort study evaluated immunologic characteristics of children with single ventricle circulation from neonatal age up to early post-Fontan period. Results: Low leukocyte counts were observed in half of the patients prior to bidirectional Glenn and Fontan surgery. Total lymphocyte counts were below normal range in 36% to 63% of patients across all groups except patients following Fontan procedure who had normal counts. Typical lymphocyte subpopulation patterns were (1) high counts of total and helper T lymphocytes (CD3+ and CD4+ cells), low B lymphocytes (CD19+ cells), and increased CD4/CD8 ratio in neonates and (2) low T lymphocytes (CD3+, CD4+, CD8+ cells) with high natural killer cells (CD16+) and B lymphocytes (CD19+ cells) in other groups. Low preoperative total lymphocyte counts were associated with longer intensive care unit stay in patients after bidirectional Glenn and Fontan procedure ( P = .03 and P = .01, respectively) and low leukocyte counts with higher incidence of pleural effusions and chylothorax after Fontan procedure ( P = .005 and P = .002, respectively). Conclusions: Single ventricle patients display several immunological abnormalities. Beyond the neonatal age, an immune pattern includes CD3+, CD4+, CD8+ lymphopenia, and CD16+ and CD19+ lymphocytosis. B-cell lymphocytosis compensates T-cell lymphopenia, producing normal total lymphocyte counts in patients early after Fontan surgery. Low preoperative total lymphocyte counts may be associated with longer postoperative intensive care unit stay in patients with bidirectional Glenn and Fontan procedure and leukopenia with pleural effusions in Fontan patients.
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Juedes, Amy E., Evelyn Rodrigo, Lisa Togher, Laurie H. Glimcher, and Matthias G. von Herrath. "T-bet Controls Autoaggressive CD8 Lymphocyte Responses in Type 1 Diabetes." Journal of Experimental Medicine 199, no. 8 (April 19, 2004): 1153–62. http://dx.doi.org/10.1084/jem.20031873.
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The T-box transcription factor T-bet is known to control lineage commitment and interferon-γ production by T helper 1 (Th1) CD4 lymphocytes. We report here that T-bet is essential for development of CD8 lymphocyte-dependent autoimmune diabetes (type 1 diabetes [T1D]) in the rat insulin promoter–lymphocytic choriomeningitis virus (LCMV) transgenic model for virally induced T1D. In the absence of T-bet, autoaggressive (anti-LCMV) CD8 lymphocytes were reduced in number and produced less IFN-γ, but increased IL-2 compared with controls. Further analysis showed that T-bet intrinsically controls the generation, but not apoptosis, maintenance, or secondary expansion of antiviral effector/memory CD8 lymphocytes. This observation points toward a therapeutic opportunity for the treatment of T1D and other autoimmune disorders.
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Lu, Zhengbin, Lingxian Yuan, Xianzheng Zhou, Eduardo Sotomayor, Hyam I. Levitsky, and Drew M. Pardoll. "Cd40-Independent Pathways of T Cell Help for Priming of Cd8+ Cytotoxic T Lymphocytes." Journal of Experimental Medicine 191, no. 3 (February 7, 2000): 541–50. http://dx.doi.org/10.1084/jem.191.3.541.
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In many cases, induction of CD8+ CTL responses requires CD4+ T cell help. Recently, it has been shown that a dominant pathway of CD4+ help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4+ T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide–specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4+ T helper cells, respectively. We found that CD4+ T cells can provide potent help for DCs to activate CD8+ T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4+ help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4+–CD8+ T cell communication via lymphokines. Therefore, we conclude that CD4+ help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4+–CD8+ T cell communication.
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JEFFERIES, WILFRED A., A. NEIL BARCLAY, JEAN GAGNON, and ALAN F. WILLIAMS. "Structure of the CD4 (W3/25) T-helper lymphocyte glycoprotein." Biochemical Society Transactions 14, no. 2 (April 1, 1986): 366. http://dx.doi.org/10.1042/bst0140366.
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Jung, Jae Wook, Ae Rin Lee, Jaesung Kim, Young Rim Kim, Jassy Mary S. Lazarte, Jung Suk Lee, Kim D. Thompson, Hyeongsu Kim, and Tae Sung Jung. "Elucidating the Functional Roles of Helper and Cytotoxic T Cells in the Cell-Mediated Immune Responses of Olive Flounder (Paralichthys olivaceus)." International Journal of Molecular Sciences 22, no. 2 (January 15, 2021): 847. http://dx.doi.org/10.3390/ijms22020847.
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In higher vertebrates, helper and cytotoxic T cells, referred to as CD4 and CD8 T lymphocytes, respectively, are mainly associated with adaptive immunity. The adaptive immune system in teleosts involves T cells equivalent to those found in mammals. We previously generated monoclonal antibodies (mAbs) against olive flounder (Paralichthys olivaceus) CD4 T cells, CD4-1 and CD4-2, and used these to describe the olive flounder’s CD4 Tcell response during a viral infection. In the present study, we successfully produced mAbs against CD8 T lymphocytes and their specificities were confirmed using immuno-blotting, immunofluorescence staining, flow cytometry analysis andreverse transcription polymerase chain reaction (RT-PCR). The results showed that these mAbs are specific for CD8 T lymphocytes. We also investigated variations in CD4 and CD8 T cells populations, and analyzed the expression of immune-related genes expressed by these cells in fish infected with nervous necrosis virus or immunized with thymus dependent and independent antigens. We found that both CD4 and CD8 T lymphocyte populations significantly increased in these fish and Th1-related genes were up-regulated compared to the control group. Collectively, these findings suggest that the CD4 and CD8 T lymphocytes in olive flounder are similar to the helper and cytotoxic T cells found in mammals, and Th1 and cytotoxic immune responses are primarily involved in the early adaptive immune response against extracellular antigens.
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Ohashi, Hiroyuki, Tadamasa Okugawa, and Mitsuyasu Itoh. "Circulating activated T cell subsets in autoimmune thyroid diseases: Differences between untreated and treated patients." Acta Endocrinologica 125, no. 5 (November 1991): 502–9. http://dx.doi.org/10.1530/acta.0.1250502.
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Abstract. To investigate the relationships between lymphocyte subsets and thyroid function, peripheral blood lymphocytes were analysed with cell surface antigens of activated (HLA-DR+) T, helper T (CD4+2H4−, CD4+4B4+) and suppressor-inducer T (CD4+2H4+, CD4+4B4−) cells subsets in 56 patients with Graves' disease, 16 patients with Hashimoto's thyroiditis, 7 patients with typical subacute thyroiditis and 2 patients with the thyrotoxic phase of autoimmune thyroiditis. Both patients with Graves' disease and Hashimoto's thyroiditis had increased percentages of HLA-DR+T (Ia+CD3+) cells as well as HLA-DR+ helper-inducer T (Ia+CD4+) cells, which seemed to be independent of treatments. The percentage of HLA-DR+ suppressor-cytotoxic T (Ia+CD8+) cells was increased in euthyroid or hypothyroid patients with Graves' disease following treatment, but was normal in hyperthyroid patients. The percentages of Ia+CD4+ cells and Ia+CD8+ were also increased in patients with thyrotoxic phases of subacute thyroiditis and autoimmune thyroiditis, whereas these abnormal values normalized in the remission phase. These findings suggest that an increase in Ia+CD4+ cells characteristically occurs during immune system activation in patients with hyperthyroid Graves' disease, Hashimoto's thyroiditis and the thyrotoxic phase of subacute thyroiditis, whereas the activated CD8+ cells in Graves' disease are induced by antithyroidal therapy.
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Forster, R., T. Emrich, E. Kremmer, and M. Lipp. "Expression of the G-protein--coupled receptor BLR1 defines mature, recirculating B cells and a subset of T-helper memory cells." Blood 84, no. 3 (August 1, 1994): 830–40. http://dx.doi.org/10.1182/blood.v84.3.830.830.
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Abstract The G-protein-coupled receptor BLR1 related to receptors for chemokines and neuropeptides has been identified as the first lymphocyte-specific member of the gene family characterized by seven transmembrane-spanning regions. Using a high-affinity anti-BLR1 monoclonal antibody (MoAb) and three-color flow cytometry it is shown that BLR1 expression on peripheral blood cells is limited to B cells and to a subset of CD4+ (14%) and CD8+ (2%) lymphocytes. T cells expressing BLR1 were positive for CD45R0, were negative for interleukin-2 receptors, show high levels of CD44, and show low levels of L-selectin. The majority of CD4+ cells originating from secondary lymphatic tissue, but none of cord blood- derived T cells, express BLR1. These observations suggest that BLR1 is a marker for memory T cells. Furthermore, BLR1 expression was detected on all CD19+ peripheral or tonsillar B lymphocytes, but only on a fraction of cord blood cells and bone marrow cells expressing CD19, sIgM, or sIgD. Interestingly, activation of both mature B and T cells by CD40 MoAb and CD3 MoAb, respectively, led to complete downregulation of BLR1. These data suggest that the G-protein-coupled receptor BLR1 is involved in functional control of mature recirculating B cells and T- helper memory cells participating in cell migration and cell activation.
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Petrichuk, S. V., L. V. Miroshkina, E. L. Semikina, A. P. Toptygina, A. S. Potapov, E. G. Tsimbalova, and T. V. Radygina. "INDIСATORS OF THE LYMPHOCYTE SUBSETS AS EFFICICIENCY PREDICTORS OF THERAPY WITH INHIBITORS OF TNFα IN CHILDREN WITH INFLAMMATORY BOWEL DISEASE." Medical Immunology (Russia) 20, no. 5 (November 6, 2018): 721–30. http://dx.doi.org/10.15789/1563-0625-2018-5-721-730.
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(IBD), who were for the first time treated with TNFα blocker (infliximab). Our aim was to determine prognostic informative value of the immunological parameters in order to assess the treatment efficiency. A comprehensive research included seventy children with IBD from 12 to 18 years old in the course of specific treatment (49 children with CD, 21 children with UC).The comparison group consisted of fifty healthy children of similar age who were subjected to a similar detailed examination. The patients were divided into two groups, depending on their therapeutic response following 1 year of biological therapy: the first group showed a persistent positive effect of the drug, and the second group exhibited only unstable effects of the treatment. We determined the contents of major and small subpopulations of peripheral blood lymphocytes before the first administration of infliximab. Immunophenotyping was performed by multicolor flow cytometry (FC 500), using the CD45, CD3, CD4, CD8, CD19, CD16, CD56, HLA-DR, CD5, CD161, CD127, CD25, and CD294 markers.We have revealed that the content of B lymphocytes was significantly reduced in children with unstable effects of therapy. By contrast, the B lymphocyte levels in children with persistent positive therapeutic effect did not differ from the comparison group. Analysis of the composition of the B lymphocyte profile showed an imbalance in the B1-to-B2 cell ratio, with decreased of B1 cell counts in IBD patients against the comparison group. In addition, the patients with unstable therapeutic effect showed a significant decrease in B2 cell numbers compared with a group with persistent effect and comparison group. The numbers of NK cells in IBD patients were found to be reduced against the comparison group. Assessment of T lymphocytes subsets revealed a number of features in the patients with minimal therapeutic effects, i.e., an increased level of activated T helper cells (CD4+CD25+CD127high) and Th17 lymphocytes (CD3+CD4+CD161+), as compared to children with stable effect of treatment and to the comparison group. Moreover, in children with minimal effects of therapy, the levels of Tregs within T-helper cell subsets were significantly higher than in the comparison group. By means of ROC analysis, we have identified most informative parameters for the groups with minimal versus persistent therapeutic effect, and showed a good quality for a discrimination model involving relative amount of Th17 cells, activated T helper cells and B lymphocytes. The number of Тh17 lymphocytes (% CD3+CD4+ lymphocytes) allowed to predict the effect of therapy with a TNFα blocker with high probability. The present study enables us to propose cellular immunity testing, as a promising tool for monitoring clinical state of IBD patients.
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Bouchama, A., K. al Hussein, C. Adra, M. Rezeig, E. al Shail, and S. al Sedairy. "Distribution of peripheral blood leukocytes in acute heatstroke." Journal of Applied Physiology 73, no. 2 (August 1, 1992): 405–9. http://dx.doi.org/10.1152/jappl.1992.73.2.405.
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We examined 11 heatstroke patients (mean rectal temperature 41.4 +/- 0.3 degrees C) and 40 healthy subjects to determine the effects of hyperthermia on peripheral blood leukocyte distribution. Precooling samples were taken on admission. Whole blood was incubated with conjugated monoclonal antibodies, and erythrocytes were eliminated by FACS lysing solution. Lymphocyte subsets were detected by specific mouse monoclonal antibodies: Leu-4/CD3+ (T-cells), Leu-3a/CD4+ (T-helper cells), Leu-2a/CD8+ (T-suppressor-cytotoxic cells), Leu-11/19/CD16+/CD56+ (natural killer cells), and Leu-12/CD19+ (B-cells). Immunofluorescence was measured with a flow cytometer. The number of circulating leukocytes and lymphocytes was significantly increased in heatstroke patients. This lymphocytosis was mainly due to an increase in T-suppressor-cytotoxic cells and natural killer cells. The absolute number of lymphocytes and T-suppressor-cytotoxic cells significantly correlated with the degree of hyperthermia (r = 0.62, P = 0.04; r = 0.751, P = 0.007, respectively). There was a significant decrease in the percentages of T-, B-, and T-helper cells and increase in T-suppressor-cytotoxic and natural killer cells, giving a marked decrease in the ratio of T-helper to T-suppressor-cytotoxic cells. We conclude that heatstroke is associated with leukocytosis and significant alteration in absolute number and percentage of circulating lymphocyte subpopulations.
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Biancone, L., G. Andres, H. Ahn, A. Lim, C. Dai, R. Noelle, H. Yagita, C. De Martino, and I. Stamenkovic. "Distinct regulatory roles of lymphocyte costimulatory pathways on T helper type-2 mediated autoimmune disease." Journal of Experimental Medicine 183, no. 4 (April 1, 1996): 1473–81. http://dx.doi.org/10.1084/jem.183.4.1473.
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We assessed the role of CD40-CD40L, cytotoxic T lymphocyte (CTL)A4/CD28-B7s, and CD2-CD48/CD58 lymphocyte costimulatory pathways in the development of mercury chloride (HgCl2)-induced autoimmune disease in mice, which is believed to be mediated by T helper (Th) subset Th2. Inhibition of CD40-CD40-L and CTLA4/CD28-B7s interactions by anti-CD40-L antibody and soluble CTLA4-immunoglobulin (Ig) fusion protein, respectively, abrogated the autoimmune disease without affecting interleukin 4 (IL-4) production, showing the importance of physical contact between T and B lymphocytes in the Th2-mediated process. In contrast, two anti-CD2 antibodies that have been shown to induce immunosuppression of Th1-mediated events exacerbated the autoantibody response and augmented IgG1, IgE, and IL-4 production, transforming a mild mesangial glomerulopathy into a severe systemic immune complex disease. These observations demonstrate that manipulation of lymphocyte accessory counterreceptor interactions may affect the course of Th2-associated autoimmune disease and suggest that signals resulting from CD2 engagement play an essential role in the regulation of the Th1-Th2 effector equilibrium.
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Fox, E. J., D. E. Lewis, K. P. Deemer, M. N. ElMasry, and R. R. Rich. "T suppressor cell growth factor and anti-CD3 antibodies stimulate reciprocal subsets of T lymphocytes." Journal of Experimental Medicine 166, no. 2 (August 1, 1987): 404–18. http://dx.doi.org/10.1084/jem.166.2.404.
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Because of the central role of IL-2 in clonal expansion of T cells, we have postulated that lymphocyte subpopulations with opposing regulatory functions might be independently regulated by differential requirements for expression of cell-surface IL-2-R. Purified CD4+ and CD8+ cells proliferated in an IL-2-dependent manner to crosslinked anti-T cell receptor antibodies (anti-CD3-Seph). Similarly, both CD4+ and CD8+ cells became IL-2 responsive after incubation in T suppressor cell growth factor (TsGF), a newly described approximately 8,000 Mr product of activated CD4+ cells. In support of our hypothesis, however, we observed that subpopulations of CD4+ and CD8+ cells, possessing distinct cell-surface antigens, showed differential responses to these stimuli. Those cells of suppressor-inducer or suppressor-effector phenotype failed to proliferate when cultured in anti-CD3-Seph plus IL-2, but did proliferate in an IL-2-dependent manner to TsGF. Furthermore, the suppressor-effector population was unresponsive to TsGF plus IL-2 when cocultured in anti-CD3-Seph, suggesting that functionally induced Ts may be refractory to growth stimuli. Conversely, cells with helper-inducer or cytolytic phenotype proliferated when incubated in anti-CD3-Seph and IL-2, while remaining essentially unresponsive to TsGF and IL-2. The results could not be explained by differences in the level of CD3 expression by the T cell subsets. Thus, cells within the helper and suppressor lineages appear to have distinct and reciprocal patterns for the induction of IL-2 responsiveness.
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Ober, Bertram T., Artur Summerfield, Christina Mattlinger, Karl-Heinz Wiesmüller, Günther Jung, Eberhard Pfaff, Armin Saalmüller, and Hanns-Joachim Rziha. "Vaccine-Induced, Pseudorabies Virus-Specific, Extrathymic CD4+CD8+ Memory T-Helper Cells in Swine." Journal of Virology 72, no. 6 (June 1, 1998): 4866–73. http://dx.doi.org/10.1128/jvi.72.6.4866-4873.1998.
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ABSTRACT Pseudorabies virus (PRV; suid herpesvirus 1) infection causes heavy economic losses in the pig industry. Therefore, vaccination with live attenuated viruses is practiced in many countries. This vaccination was demonstrated to induce extrathymic virus-specific memory CD4+CD8+ T lymphocytes. Due to their major histocompatibility complex (MHC) class II-restricted proliferation, it is generally believed that these T lymphocytes function as memory T-helper cells. To directly prove this hypothesis, 15-amino-acid, overlapping peptides of the viral glycoprotein gC were used for screening in proliferation assays with peripheral blood mononuclear cells of vaccinated d/d haplotype inbred pigs. In these experiments, two naturally processed T-cell epitopes (T1 and T2) which are MHC class II restricted were identified. It was shown that extrathymic CD4+CD8+ T cells are the T-lymphocyte subpopulation that responds to epitope T2. In addition, we were able to show that cytokine secretion can be induced in these T cells through recall with inactivated PRV and demonstrated that activated PRV-primed CD4+CD8+ T cells are able to induce PRV-specific immunoglobulin synthesis by PRV-primed, resting B cells. Taken together, these results demonstrate that the glycoprotein gC takes part in the priming of humoral anti-PRV memory responses. The experiments identified the first T-cell epitopes so far known to induce the generation of virus-specific CD4+CD8+ memory T lymphocytes and showed that CD4+CD8+ T cells are memory T-helper cells. Therefore, this study describes the generation of virus-specific CD4+CD8+ T cells, which is observed during vaccination, as a part of the potent humoral anti-PRV memory response induced by the vaccine.
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Inaba, K., J. W. Young, and R. M. Steinman. "Direct activation of CD8+ cytotoxic T lymphocytes by dendritic cells." Journal of Experimental Medicine 166, no. 1 (July 1, 1987): 182–94. http://dx.doi.org/10.1084/jem.166.1.182.
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Recent experiments (11-13) have shown that antigen-specific, CD8+, CD4- T lymphocytes can be induced to proliferate and become killer cells in the absence of a second population of "helper" CD8-, CD4+ cells. We have studied early events in the activation of CD4+ and CD8+ T cell subsets in the primary mixed leukocyte reaction. Dendritic cells are a major if not essential accessory cell for the activation of both subpopulations. Antigen-bearing macrophages fail to stimulate unprimed CD8+ cells, but act as targets for the sensitized cytolytic lymphocytes that are induced by dendritic cells. The initial proliferative response is comparable for CD4+ and CD8+ lymphocyte subsets. For both subpopulations, dendritic cells efficiently cluster the responding lymphocytes on the first day and induce the release of IL-2. The data indicate that CD4+ and CD8+ lymphocytes can be activated by a similar mechanism, and illustrate the special role of dendritic cells in the sensitization stage of cell-mediated immunity.
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Legac, E., B. Autran, H. Merle-Beral, C. Katlama, and P. Debre. "CD4+CD7-CD57+ T cells: a new T-lymphocyte subset expanded during human immunodeficiency virus infection." Blood 79, no. 7 (April 1, 1992): 1746–53. http://dx.doi.org/10.1182/blood.v79.7.1746.1746.
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Abstract CD7 and CD57 are two cell surface molecules related to the differentiation or functional stages of CD4+ T cells. The CD4+CD7- T cells represent a minor subset of CD4+ cells in normal individuals and are considered to contain the normal counterpart of Sezary T cells; the CD4+CD57+ peripheral blood lymphocytes (PBL) are detectable in long- term renal allograft recipients. We compared the cell surface expression of these CD7 and CD57 markers on CD4+ T lymphocytes in peripheral blood and lymphoid organs from normal individuals and human immunodeficiency virus (HIV)-infected patients. Our results indicate that CD4+CD7- T cells in normal PBL do not express CD57 and were poorly responsive to anti-CD3 monoclonal antibody (MoAb), the activation being restored by addition of anti-CD28 MoAb. This CD4+CD7- cell subset is increased in peripheral blood during HIV infection, and its progressive expansion mirrors both the absolute and relative decrease of CD4+ T cells. The lack of CD7 expression is correlated with CD57 acquisition on CD4+ T cells because CD4+CD7-CD57+ cells represent a major component of the CD4+CD7- subset in HIV-infected patients. Our results suggest that the presence and the expansion of CD4+CD7-CD57+ T lymphocytes, which do not behave as previously defined helper subsets, may participate to the immune dysfunction observed during HIV infection.
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Legac, E., B. Autran, H. Merle-Beral, C. Katlama, and P. Debre. "CD4+CD7-CD57+ T cells: a new T-lymphocyte subset expanded during human immunodeficiency virus infection." Blood 79, no. 7 (April 1, 1992): 1746–53. http://dx.doi.org/10.1182/blood.v79.7.1746.bloodjournal7971746.
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CD7 and CD57 are two cell surface molecules related to the differentiation or functional stages of CD4+ T cells. The CD4+CD7- T cells represent a minor subset of CD4+ cells in normal individuals and are considered to contain the normal counterpart of Sezary T cells; the CD4+CD57+ peripheral blood lymphocytes (PBL) are detectable in long- term renal allograft recipients. We compared the cell surface expression of these CD7 and CD57 markers on CD4+ T lymphocytes in peripheral blood and lymphoid organs from normal individuals and human immunodeficiency virus (HIV)-infected patients. Our results indicate that CD4+CD7- T cells in normal PBL do not express CD57 and were poorly responsive to anti-CD3 monoclonal antibody (MoAb), the activation being restored by addition of anti-CD28 MoAb. This CD4+CD7- cell subset is increased in peripheral blood during HIV infection, and its progressive expansion mirrors both the absolute and relative decrease of CD4+ T cells. The lack of CD7 expression is correlated with CD57 acquisition on CD4+ T cells because CD4+CD7-CD57+ cells represent a major component of the CD4+CD7- subset in HIV-infected patients. Our results suggest that the presence and the expansion of CD4+CD7-CD57+ T lymphocytes, which do not behave as previously defined helper subsets, may participate to the immune dysfunction observed during HIV infection.
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Borisevich, G. V., S. L. Kirillova, O. N. Sidorova, V. N. Lebedev, A. A. Petrov, A. V. Ovchinnikov, I. V. Shatokhina, et al. "Analysis of Cellular Component Indicators of Immune Status of Rhesus Macaques." Problems of Particularly Dangerous Infections, no. 4 (February 7, 2021): 41–46. http://dx.doi.org/10.21055/0370-1069-2020-4-41-46.
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Objective. Selection of indicators of lymphocyte populations in rhesus macaques determined by flow cytometry to evaluate variations of cellular constituent of their immune status.Materials and methods. Blood of 11 healthy rhesus macaque males, 2,0–2,5 years old, weighing 2,5–3,0 kg, was used. Monkeys were examined simultaneously in each of 7 months of observation (since May till November). Immunophenotyping was conducted by FC500 cytofluorimeter using Affymetrix eBioscience monoclonal antibodies. The following cellular constituent indicators of immune status were differentiated: total T lymphocytes (phenotype CD2+CD20-); total B lymphocytes (phenotype CD2-CD20+); natural killer cells (phenotype CD2+CD56+); T helper cells (phenotype CD2+CD4+); cytotoxic T lymphocytes (phenotype CD2+CD8+); double-positive T lymphocytes (phenotype CD4+CD8+) and T lymphocytes positive by antigens CD2 and CD20 (phenotype CD2+CD20+).Results and discussion. Statistical analysis of the obtained results revealed the absence of the effect of research time factor on the stated indicators. To assess changes in the cellular constituent of immune status of rhesus macaques, it is possible to use indicators that are less variable: total T and B lymphocytes, T helper cells, cytotoxic T lymphocytes and T lymphocytes with phenotype (CD2+CD20+). The use of CD56 as a marker of natural killer cells of rhesus macaques is impractical due to its low expression and a small size of the population bearing this marker. The research results may form the basis of the normative indicators of the subpopulation cell composition of immune system in rhesus macaques, which will allow the study of infected animals when assessing the quality of medical products in relation to dangerous and particularly dangerous infections.
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Symeonidis, Argiris S., George Theodorou, Constantina Repa, Theodore Marinakis, Panayiotis Tsaftaridis, Alexandra Kouraklis, Marina Karakantza, and Nicholas Zoumbos. "Impaired T-Lymphocyte Subpopulations and Deranged Profile of Immunologic Activation in Patients with Gaucher Disease Type I." Blood 112, no. 11 (November 16, 2008): 4915. http://dx.doi.org/10.1182/blood.v112.11.4915.4915.
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Abstract Patients with Gaucher disease exhibit substantial evidence of impairment of their immune system, namely, increased serum levels of proinflammatory cytokines and immunoglobulins, and increased incidence of B-cell malignancies, such as non-Hodgkin’s lymphoma, MGUS and multiple myeloma. We investigated peripheral blood T-lymphocyte subpopulations with dual color flow cytometry, as well as the direction of T-lymphocyte activation, by using intracytoplasmic immunostaining for IL-2, IL-4, IL-10 and IFN-gamma, on resting CD4+ and CD8+ T-lymphocytes and following activation with PMA- 1 with the presence of Brefeldin-A. Evaluations were performed on 16 patients with type I Gaucher disease and on 17 healthy controls. Patients had significantly decreased absolute lymphocyte count (1621±684 vs 2148±566/mm3, p=0.013), CD3+ (1197±478 vs 1508±431/mm3, p=0.045) and CD4+ T-lymphocytes (658±245 vs 945±253/mm3, p=0.021), but not CD8+ T-lymphocytes (491±331 vs 486±189/mm3, p: n.s.), resulting in a significant reduction of the CD4/CD8 ratio (1.59±0.68 vs 2.16±0.83, p=0.041). The populations of naive CD4+CD45RA+ and of memory CD4+CD45RO+ T-lymphocytes were also significantly decreased (218±128 vs 432±179/mm3, p=0.0005 and 484±185 vs 631±231/mm3, p=0.056 respectively), however, CD8+CD45RA+ and CD8+CD45RO+ subpopulations did nor differ significantly, when compared to controls. CD3−CD56+, but not CD3+CD56+ lymphocytes were also decreased (131±82 vs 199±97/mm3, p=0.037). Patients had higher percentages of CD8+ (29.2±9.7 vs 23.5±6.8%, p=0.042), CD8+CD45RA+ (22.1±6.2 vs 18.3±5.0%, p=0.046) and CD8+CD45RO+ T-lymphocytes (13.2±6.2 vs 9.6±3.7%, p=0.027), as well as of activated CD8+HLA-DR+ (0.93±0.68 vs 0.48±0.21%, p=0.008) and CD4+HLA-DR+ T-lymphocytes (1.77±0.93 vs 1.09±0.48%, p=0.008). Moreover, although both, the absolute number and the percentage of CD20+ B-lymphocytes were similar, patients exhibited significantly increased absolute number and percentage of CD5+CD20+ B-lymphocytes (1.63±0.55 vs 0.64±0.37% p=0.00002 and 29±20 vs 13±8/mm3, p=0.011, respectively). Finally, patients with Gaucher disease had significantly increased resting TH2-polarized CD4+T-lymphocytes (CD4+IL-10+: 0.41±0.29 vs 0.24±0.11%, p=0.045) and TH1-polarized CD8+ T-lymphocytes (CD8+IFNγ+: 0.15±0.07 vs 0.08±0.04%, p=0.005, CD8+IL10+: 0.22±0.08 vs 0.32±0.014, p=0.052, and IFNγ+/IL4+ ratio among the CD8+ population 2.54±2.1 vs 1.08±0.91, p=0.018). Following mitogenic activation a very significant impairment of obtaining the TH1 phenotype was observed (CD4+IL2+ lymphocytes 33.7±17.1 vs 65.4±6.1%, p<0.00001). The above findings suggest that in patients with Gaucher disease there is a significant numerical impairment of T-helper lymphocytes and a shift towards TH-2 direction of lymphocyte activation. These findings may explain the rarity of autoimmune manifestations despite the chronic inflammatory reaction, as well as the increased incidence of lymphoid malignancies, which has been reported among patients suffering from this disease.
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Wald, N., A. Legat, C. Meyer, D. E. Speiser, and E. Goormaghtigh. "An infrared spectral signature of human lymphocyte subpopulations from peripheral blood." Analyst 140, no. 7 (2015): 2257–65. http://dx.doi.org/10.1039/c4an02247e.
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Takeuchi, Arata, Mohamed El Sherif Gadelhaq Badr, Kosuke Miyauchi, Chitose Ishihara, Reiko Onishi, Zijin Guo, Yoshiteru Sasaki, et al. "CRTAM determines the CD4+ cytotoxic T lymphocyte lineage." Journal of Experimental Medicine 213, no. 1 (December 22, 2015): 123–38. http://dx.doi.org/10.1084/jem.20150519.
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Naive T cells differentiate into various effector T cells, including CD4+ helper T cell subsets and CD8+ cytotoxic T cells (CTL). Although cytotoxic CD4+ T cells (CD4+CTL) also develop from naive T cells, the mechanism of development is elusive. We found that a small fraction of CD4+ T cells that express class I–restricted T cell–associated molecule (CRTAM) upon activation possesses the characteristics of both CD4+ and CD8+ T cells. CRTAM+ CD4+ T cells secrete IFN-γ, express CTL-related genes, such as eomesodermin (Eomes), Granzyme B, and perforin, after cultivation, and exhibit cytotoxic function, suggesting that CRTAM+ T cells are the precursor of CD4+CTL. Indeed, ectopic expression of CRTAM in T cells induced the production of IFN-γ, expression of CTL-related genes, and cytotoxic activity. The induction of CD4+CTL and IFN-γ production requires CRTAM-mediated intracellular signaling. CRTAM+ T cells traffic to mucosal tissues and inflammatory sites and developed into CD4+CTL, which are involved in mediating protection against infection as well as inducing inflammatory response, depending on the circumstances, through IFN-γ secretion and cytotoxic activity. These results reveal that CRTAM is critical to instruct the differentiation of CD4+CTL through the induction of Eomes and CTL-related gene.
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Staska, Lauren M., Christopher J. Davies, Wendy C. Brown, Travis C. McGuire, Carlos E. Suarez, Joo Youn Park, Bruce A. Mathison, Jeffrey R. Abbott, and Timothy V. Baszler. "Identification of Vaccine Candidate Peptides in the NcSRS2 Surface Protein of Neospora caninum by Using CD4+ Cytotoxic T Lymphocytes and Gamma Interferon-Secreting T Lymphocytes of Infected Holstein Cattle." Infection and Immunity 73, no. 3 (March 2005): 1321–29. http://dx.doi.org/10.1128/iai.73.3.1321-1329.2005.
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ABSTRACT Previously, our laboratory showed that Holstein cattle experimentally infected with Neospora caninum develop parasite-specific CD4+ cytotoxic T lymphocytes (CTL) that lyse infected, autologous target cells through a perforin-granzyme pathway. To identify specific parasite antigens inducing bovine CTL and helper T-lymphocyte responses for vaccine development against bovine neosporosis, the tachyzoite major surface proteins NcSAG1 and NcSRS2 were targeted. In whole tachyzoite antigen-expanded bovine T-lymphocyte lines, recombinant NcSRS2 induced potent memory CD4+- and CD8+-T-lymphocyte activation, as indicated by proliferation and gamma interferon (IFN-γ) secretion, while recombinant NcSAG1 induced a minimal memory response. Subsequently, T-lymphocyte epitope-bearing peptides of NcSRS2 were mapped by using overlapping peptides covering the entire NcSRS2 sequence. Four experimentally infected cattle with six different major histocompatibility complex (MHC) class II haplotypes were the source of immune cells used to identify NcSRS2 peptides presented by Holstein MHC haplotypes. NcSRS2 peptides were mapped by using IFN-γ secretion by rNcSRS2-stimulated, short-term T-lymphocyte cell lines, IFN-γ enzyme-linked immunospot (ELISPOT) assay with peripheral blood mononuclear cells, and 51Cr release cytotoxicity assay of rNcSRS2-stimulated effector cells. Four N. caninum-infected Holstein cattle developed NcSRS2 peptide-specific T lymphocytes detected ex vivo in peripheral blood by IFN-γ ELISPOT and in vitro by measuring T-lymphocyte IFN-γ production and cytotoxicity. An immunodominant region of NcSRS2 spanning amino acids 133 to 155 was recognized by CD4+ T lymphocytes from the four cattle. These findings support investigation of subunit N. caninum vaccines incorporating NcSRS2 gene sequences or peptides for induction of NcSRS2 peptide-specific CTL and IFN-γ-secreting T lymphocytes in cattle with varied MHC genotypes.
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Denkers, E. Y., T. Scharton-Kersten, S. Barbieri, P. Caspar, and A. Sher. "A role for CD4+ NK1.1+ T lymphocytes as major histocompatibility complex class II independent helper cells in the generation of CD8+ effector function against intracellular infection." Journal of Experimental Medicine 184, no. 1 (July 1, 1996): 131–39. http://dx.doi.org/10.1084/jem.184.1.131.
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Major histocompatibility complex (MHC) class II (A beta) knockout mice were vaccinated with ts-4, an attenuated mutant strain of Toxoplasma gondii, which in normal animals induces strong T cell immunity mediated by interferon gamma (IFN-gamma). After challenge with the lethal parasite strain RH, the knockout mice displayed decreased resistance consistent with absence of CD4+ effectors. Nevertheless, these animals generated CD8+ lymphocyte effectors capable of mediating partial protection through IFN-gamma secretion. Moreover, in vivo neutralization experiments indicated that the development of resistance in knockout mice depends on CD4+ cells as well as interleukin 2 (IL-2). The identity of the IL-2-producing protective cell population was further characterized as CD4+, NK1.1+ by in vitro depletion studies and reverse transcriptase-PCR analysis of fluorescence-activated cell sorter (FACS)-purified CD4+ NK1.1+ T lymphocytes. These results demonstrate that in the absence of conventional MHC class II-restricted CD4+ T lymphocytes, CD8 priming persists and mediates partial protective immunity to T. gondii. Moreover, the data argue that CD4+, NK1.1+ cells, previously implicated in the initiation of T helper cell 2 (Th2) responses through their production of IL-4, can also play a role as alternative IL-2-secreting helper cells in Th1-mediated host resistance to infection.
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Figueiredo, Constança, Miriam Wittmann, Dong Wang, Ralf Dressel, Axel Seltsam, Rainer Blasczyk, and Britta Eiz-Vesper. "Heat shock protein 70 (HSP70) induces cytotoxicity of T-helper cells." Blood 113, no. 13 (March 26, 2009): 3008–16. http://dx.doi.org/10.1182/blood-2008-06-162727.
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Abstract Heat shock protein 70 (HSP70) has gained plenty of attention because of its adjuvant capability to induce CD8+ cytotoxic T lymphocyte and CD4+ T-helper cell responses. We investigated the behavior of T-cell subsets stimulated with endotoxin-free HSP70 with respect to proliferation, cytokine expression, cytotoxicity against allogeneic B-lymphoblastoid cell line and K562 cells, as well as target-independent cytotoxicity. CD4+ cells exhibited a strong increase in proliferation after stimulation with HSP70 (29%). In the presence of targets, a 35-fold up-regulation of granzyme B was observed after stimulation of CD4+ T cells with HSP70 in combination with interleukin-7 (IL-7)/IL-12/IL-15. The target cell-independent secretion of granzyme B by CD4+ cells was greatly augmented after stimulation with HSP70 plus IL-2 or IL-7/IL-12/IL-15. In this study, we showed that HSP70 is capable of inducing a cytotoxic response of T-helper cells in the absence of lipopolysaccharide. The granzyme B secretion and cytolytic activity of T-helper cells are induced in a target-independent way, whereas the cytotoxic activity of CD3+ and CD8+ T cells can be further enhanced in the presence of target cells. Our data provide novel insights into the role of extracellular HSP70 on T-cell immune response concerning the induction of target-independent T-helper cell cytotoxicity.
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Lonning, S. M., W. Zhang, and T. C. McGuire. "Gag Protein Epitopes Recognized by CD4+T-Helper Lymphocytes from Equine Infectious Anemia Virus-Infected Carrier Horses." Journal of Virology 73, no. 5 (May 1, 1999): 4257–65. http://dx.doi.org/10.1128/jvi.73.5.4257-4265.1999.
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ABSTRACT Antigen-specific T-helper (Th) lymphocytes are critical for the development of antiviral humoral responses and the expansion of cytotoxic T lymphocytes (CTL). Identification of relevant Th lymphocyte epitopes remains an important step in the development of an efficacious subunit peptide vaccine against equine infectious anemia virus (EIAV), a naturally occurring lentivirus of horses. This study describes Th lymphocyte reactivity in EIAV carrier horses to two proteins, p26 and p15, encoded by the relatively conserved EIAV gag gene. Using partially overlapping peptides, multideterminant and possibly promiscuous epitopes were identified within p26. One peptide was identified which reacted with peripheral blood mononuclear cells (PBMC) from all five EIAV-infected horses, and three other peptides were identified which reacted with PBMC from four of five EIAV-infected horses. Four additional peptides containing both CTL and Th lymphocyte epitopes were also identified. Multiple epitopes were recognized in a region corresponding to the major homology region of the human immunodeficiency virus, a region with significant sequence similarity to other lentiviruses including simian immunodeficiency virus, puma lentivirus, feline immunodeficiency virus, Jembrana disease virus, visna virus, and caprine arthritis encephalitis virus. PBMC reactivity to p15 peptides from EIAV carrier horses also occurred. Multiple p15 peptides were shown to be reactive, but not all infected horses had Th lymphocytes recognizing p15 epitopes. The identification of peptides reactive with PBMC from outbred horses, some of which encoded both CTL and Th lymphocyte epitopes, should contribute to the design of synthetic peptide or recombinant vector vaccines for EIAV.
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Wen, Yi, Nathan P. Rudemiller, Jiandong Zhang, Taylor Robinette, Xiaohan Lu, Jiafa Ren, Jamie R. Privratsky, Sergei A. Nedospasov, and Steven D. Crowley. "TNF-α in T lymphocytes attenuates renal injury and fibrosis during nephrotoxic nephritis." American Journal of Physiology-Renal Physiology 318, no. 1 (January 1, 2020): F107—F116. http://dx.doi.org/10.1152/ajprenal.00347.2019.
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Nephrotoxic serum nephritis (NTN) models immune-mediated human glomerulonephritis and culminates in kidney inflammation and fibrosis, a process regulated by T lymphocytes. TNF-α is a key proinflammatory cytokine that contributes to diverse forms of renal injury. Therefore, we posited that TNF-α from T lymphocytes may contribute to NTN pathogenesis. Here, mice with T cell-specific deletion of TNF-α (TNF TKO) and wild-type (WT) control mice were subjected to the NTN model. At 14 days after NTN, kidney injury and fibrosis were increased in kidneys from TNF TKO mice compared with WT mice. PD1+CD4+ T cell numbers and mRNA levels of IL-17A were elevated in NTN kidneys of TNF TKO mice, suggesting that augmented local T helper 17 lymphocyte responses in the TNF TKO kidney may exaggerate renal injury and fibrosis. In turn, we found increased accumulation of neutrophils in TNF TKO kidneys during NTN. We conclude that TNF-α production in T lymphocytes mitigates NTN-induced kidney injury and fibrosis by inhibiting renal T helper 17 lymphocyte responses and infiltration of neutrophils.
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Elliott, Lucinda H., William H. Brooks, and Thomas L. Roszman. "Activation of immunoregulatory lymphocytes obtained from patients with malignant gliomas." Journal of Neurosurgery 67, no. 2 (August 1987): 231–36. http://dx.doi.org/10.3171/jns.1987.67.2.0231.
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✓ The responsiveness of T cells and their subsets (T-helper cells and T-suppressor cells) obtained from patients with malignant gliomas was evaluated in an effort to further define the mechanism of their impaired host immunocompetence. This study demonstrates that peripheral blood lymphocytes obtained from these patients have impaired responsiveness to a variety of mitogens including phytohemagglutinin, concanavalin A, pokeweed mitogen, and anti-T3 monoclonal antibody. The impaired lymphocyte responsiveness does not result from the inability of these cells to express receptors for a specific mitogen or antibody. The mitogenic responsiveness of purified T cells is markedly reduced when compared to values obtained from control subjects. Therefore, the decreased T cell reactivity of patients with malignant gliomas does not result simply from a diminution in the absolute number of potentially responding lymphocytes. The mitogen reactivity of the T cell subsets, CD4+ helper cells, and CD8+ cytotoxic/suppressor cells was also investigated. These results demonstrate that the responsiveness of the CD4+ T-helper cell subset obtained from these patients is consistently diminished as compared to control values. In contrast, the reactivity of the CD8+ T cell subset was not nearly as dramatically impaired. Thus, these results indicate that the proliferative defect observed in T cells obtained from patients is located predominantly in the T-helper cell subset. Functional deficiencies in this important subpopulation of T lymphocytes may explain, in part, the presence of depressed immune responsiveness in patients with malignant glial tumors.
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Baltadzhiev, Ivan G., and Pavel I. Pavlov. "Clinical Investigations. T-Lymphocyte Subset Absolute Counts in the Peripheral Blood of Mediterranean Spotted Fever Patients: Relations to Disease Severity / Абсолютное Количество Субпопуляций Т-Лимфоцитов В Перифери- Ческой Крови Пациентов Со Средиземноморской Пятнистой Лихо- Радкой: Установление Связи С Тяжестью Заболевания." Folia Medica 57, no. 2 (June 1, 2015): 93–103. http://dx.doi.org/10.1515/folmed-2015-0026.
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AbstractINTRODUCTION: Mediterranean spotted fever (MSF) in Bulgaria is caused by Rickettsia conorii conorii. Aim: This study aims at investigating the absolute counts of T-lymphocyte subsets in the peripheral blood of patients with MSF in order to establish relationships with disease severity. MATERIALS AND METHODS: The absolute counts of T-lymphocyte subsets were tested in the blood of 62 patients in the acute stage of MSF. They were assigned into three age and sex matched groups, based on the severity of disease - with mild, moderate or severe forms. Controls were 32 age and sex matched healthy individuals. The diagnosis was confirmed by an immunofluorescence assay. Immunophenotyping was performed using Epics XL-MCL Coulter, USA flow-cytometer. RESULTS: The absolute counts of immune competent (CD3+) cells, as well as the counts of helper/inducer (CD3+CD4+) and suppressor/ cytotoxic (CD3+CD8+) T-cell subsets decreased in parallel with disease severity. Naïve (CD4+CD45RA+) and activated memory (CD4+CD45RO+) T-cell subsets were reduced, particularly in severe MSF. Taken as a whole, the counts of activated (CD3+HLA-DR+) and that of presenting accessory (CD28+) or stimulatory (CD38+) molecules Т-cell subsets was increased, but in the first two subsets the trend from mild to severe forms of the disease was descending. CONCLUSION: Reduced T-lymphocyte subset counts are likely related to trans-migration into perivascular inflammatory foci. The increased number of T-lymphocytes bearing activation molecules reflects a mobilization of the cell-mediated immune response. An important issue of this study is the possible prognostic value of T-cell subsets counting, predicting the evolution of a clinical condition to clinical forms, according to the disease severity.
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Shoker, A., R. Miller, R. Uldall, E. Friedman, S. Angra, and C. J. Cardella. "Lack of enhanced T-helper cell function in uremic patients with circulating alloreactive antibodies." Journal of the American Society of Nephrology 5, no. 7 (January 1995): 1441–50. http://dx.doi.org/10.1681/asn.v571441.
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Some uremic patients with a history of blood transfusion, pregnancy, and previous transplantation maintain high levels of alloreactive cytotoxic antibodies in the absence of continuous exogenous allogenic stimuli and are thus considered sensitized to the major histocompatibility proteins. To differentiate into antibody-producing cells, B lymphocytes must interact with T-helper (CD4+) cells. Whether ongoing help from these cells is necessary for the B cells to continue producing cytotoxic alloreactive antibodies in these sensitized uremic patients is unknown. To gain insight into the cellular mechanisms that are associated with sustained alloantibody production, T cell activation markers were measured and specific and nonspecific T-helper cell function was studied in three uremic groups with different levels of panel reactive antibodies: 10 patients whose sera reacted to more than 80% of a panel of normal lymphocytes for at least 6 months before the study were highly sensitized, 20 patients whose sera reacted to less than 80% of the panel were moderately sensitized, and 10 nonsensitized patients whose sera did not react to any cell on the panel. The number of total and activated T-helper cells was similar in the highly sensitized and nonsensitized patients. Peripheral blood lymphocyte proliferation in response to plant lectins, soluble OKT3, or alloantigens was similar in the three uremic groups. The spontaneous proliferation of pure T-helper cells and proliferative responses to immobilized OKT3 or alloantigens were also similar in highly sensitized and nonsensitized patients. Alloreactive interleukin-2-producing cell frequencies with pure CD4+ cells as responding cells were 771 +/- 77.9/10(6) cells in highly sensitized, 945 +/- 252/10(6) cells in nonsensitized, and 973 +/- 114/10(6) cells in controls (P = not significant). Panel reactive antibody levels did not correlate with any of the measures of T helper responses. There was a significant decrease of peripheral blood lymphocyte responses to alloantigens and anti-CD3 antibody in all uremic patients as compared with normals, suggesting a dysfunction in accessory cells that was quantitatively similar in sensitized and nonsensitized patients. In spite of the continuous production of alloantibodies by B cells, there is no evidence of either specific or nonspecific enhancement of T-helper cell function in sensitized patients. The absence of T cell immunity to alloantigens suggests that sustained activation of T-helper cells with subsequent interleukin-2 production is not necessary to maintain alloreactive B cell function.
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Ossendorp, Ferry, Erica Mengedé, Marcel Camps, Rian Filius, and Cornelis J. M. Melief. "Specific T Helper Cell Requirement for Optimal Induction of Cytotoxic T Lymphocytes against Major Histocompatibility Complex Class II Negative Tumors." Journal of Experimental Medicine 187, no. 5 (March 2, 1998): 693–702. http://dx.doi.org/10.1084/jem.187.5.693.
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This study shows that induction of tumor-specific CD4+ T cells by vaccination with a specific viral T helper epitope, contained within a synthetic peptide, results in protective immunity against major histocompatibility complex (MHC) class II negative, virus-induced tumor cells. Protection was also induced against sarcoma induction by acutely transforming retrovirus. In contrast, no protective immunity was induced by vaccination with an unrelated T helper epitope. By cytokine pattern analysis, the induced CD4+ T cells were of the T helper cell 1 type. The peptide-specific CD4+ T cells did not directly recognize the tumor cells, indicating involvement of cross-priming by tumor-associated antigen-presenting cells. The main effector cells responsible for tumor eradication were identified as CD8+ cytotoxic T cells that were found to recognize a recently described immunodominant viral gag-encoded cytotoxic T lymphocyte (CTL) epitope, which is unrelated to the viral env-encoded T helper peptide sequence. Simultaneous vaccination with the tumor-specific T helper and CTL epitopes resulted in strong synergistic protection. These results indicate the crucial role of T helper cells for optimal induction of protective immunity against MHC class II negative tumor cells. Protection is dependent on tumor-specific CTLs in this model system and requires cross-priming of tumor antigens by specialized antigen-presenting cells. Thus, tumor-specific T helper epitopes have to be included in the design of epitope-based vaccines.
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Rodríguez, S. D., G. H. Palmer, T. F. McElwain, T. C. McGuire, B. J. Ruef, M. G. Chitko-McKown, and W. C. Brown. "CD4+ T-helper lymphocyte responses against Babesia bigemina rhoptry-associated protein I." Infection and immunity 64, no. 6 (1996): 2079–87. http://dx.doi.org/10.1128/iai.64.6.2079-2087.1996.
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Bonder, Claudine S., Stephen R. Clark, M. Ursula Norman, Pauline Johnson, and Paul Kubes. "Use of CD44 by CD4+ Th1 and Th2 lymphocytes to roll and adhere." Blood 107, no. 12 (June 15, 2006): 4798–806. http://dx.doi.org/10.1182/blood-2005-09-3581.
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AbstractLocalization of circulating lymphocytes to a site of inflammation is paramount for the development and maintenance of an immune response. In vitro studies using cell lines have previously demonstrated that rolling and adhesion of lymphocytes on endothelium requires CD44 interactions with hyaluronan (HA). To date, whether CD44 has a role in mediating CD4+-polarized T-helper 1 (Th1) and Th2 lymphocyte interactions with the endothelium in vivo is yet to be determined. In this study we used intravital microscopy to demonstrate that both Th1 and Th2 lymphocytes use CD44 to roll and adhere to tumor necrosis factor-α (TNFα)–activated microvasculature. Furthermore, chimeric studies imply that CD44 expression by both the endothelium and lymphocytes is essential for these interactions to occur. HA was also necessary for T cell–endothelial cell interactions in vivo and Th1 and Th2 cells rolled on immobilized HA in vitro via CD44. In vitro, both Th1 and Th2 lymphocytes have increased expression of CD44 and greater binding of fluorescent HA than naive cells. The interactions of Th1 and Th2 cells were entirely dependent upon both P-selectin and CD44 in vivo, but did not appear to be counter ligands in vitro. Taken together, these results suggest that CD44 and HA are key to both Th1 and Th2 lymphocyte interactions with the TNFα-activated endothelium and raises the possibility of cooperativity between the P-selectin/PSGL-1 and HA/CD44 pathways for Th1 and Th2 rolling in vivo.
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Ceylan, Ayca, Mehmet Artac, and Hasibe Artac. "Increased PD-1 and EGFR expression levels of T lymphocytes in patients with non-small cell lung cancer." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e21018-e21018. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e21018.
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e21018 Background: Programmed cell death protein 1 (PD-1) and its ligand (PD-L1) are proteins that negatively regulate immune responses. Increased expression of PD-L1 in cancer cells leads to inhibition of the immune response against cancer, and causes cancer development and metastasis. Epidermal growth factor receptor (EGFR) activation upregulates PD-L1 expression in lung cancer cells and contribute to escape from immune response. In this study, we aimed to investigate the circulating T lymphocyte subsets and, PD-1 and EGFR expression levels of these cells in non-small cell lung cancer (NSCLC) progression. Methods: 40 NSCLC patients with 63.8 ± 8.0 mean age and 40 healthy controls with 60.9 ± 14.6 mean age were included in the study. In the peripheral blood samples of the patients taken at the time of diagnosis and controls, CD4+ T helper (Th) subsets (Th1, Th2, Th9, Th17, Th1Th17, CD4+ follicular T [Tfc] and peripheral T cells [Tpcs]), CD8+ cytotoxic T cell (CTL) subsets (CD8+ Tfcs and Tpcs), EGFR and PD-1 expression levels of T cells were determined by flow cytometric analysis. Results: Total lymphocyte ratio was decreased in patients with NSCLC compared to control (11.5 ± 5.2 in patients and 17.6 ± 6.1 in controls, p = 0.001), but there was no significant difference in CD3+ total T, Th and CTLs as well as their subsets (p < 0.05). Increased PD-1 expression level (mean fluorescence intensity-MFI) on total lymphocyte (p = 0.001), CD3+ T (p = 0.001), CD4+ Th (p = 0.001), CTL (p = 0.016), CD4+ Tpc (p = 0.002) and CD8+ Tpc subsets (p = 0.017) were determined in the patients compared with controls. EGFR expressions were also increased on total lymphocyte, CD3+ T, Th and Th2 cells (p = 0.034, p = 0.020, p = 0.030, respectively). 19 NSCLC patients were metastatic, while 21 patients were non-metastatic. There was no significant difference in mean age between metastatic and non-metastatic NSCLC patients. Reduced total lymphocytes and Th cells, increased Th1Th17 cells were found in metastatic NSCLC patients (p = 0.003, p = 0.046 and p = 0.022, respectively). The percentage of EGFR in CD3+ T cell and Th17 cells decreased in metastatic patients. Conclusions: This study showed the increased PD-1 and EGFR expression levels of T lymphocytes in patients with NSCLC. Cancer cells may upregulate PD-1 expression by inducing EGFR activation on lymphocytes to suppress immune responses, leading to programmed cell death of lymphocytes and a decrease in the percentage of these cells in NSCLC. Therapeutic approaches focused on changing EGFR need to be considered for the distribution of T cell subsets and EGFR expressions.
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Bennett, Sally R. M., Francis R. Carbone, Freda Karamalis, Jacques F. A. P. Miller, and William R. Heath. "Induction of a CD8+ Cytotoxic T Lymphocyte Response by Cross-priming Requires Cognate CD4+ T Cell Help." Journal of Experimental Medicine 186, no. 1 (July 7, 1997): 65–70. http://dx.doi.org/10.1084/jem.186.1.65.
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Class I–restricted presentation is usually associated with cytoplasmic degradation of cellular proteins and is often considered inaccessible to exogenous antigens. Nonetheless, certain exogenous elements can gain entry into this so-called endogenous pathway by a mechanism termed cross-presentation. This is known to be effective for class I–restricted cytotoxic T lymphocyte (CTL) cross-priming directed against a variety of exogenous tumor, viral, and minor transplantation antigens. The related effect of cross-tolerance can also effectively eliminate responses to selected self components. In both cases, this presentation appears to require the active involvement of a bone marrow–derived antigen presenting cell (APC). Here, we show that CTL induction by cross-priming with cell-associated ovalbumin requires the active involvement of CD4+ helper T cells. Importantly, this CD4+ population is only effective when both the helper and CTL determinants are recognized on the same APC. Moreover, we would argue that the cognitive nature of this event suggests that the CD4+ T cell actively modifies the APC, converting it into an effective stimulator for the successful priming of the CTL precursor.
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Bergner, Raoul, Burkhard Weiss, Martin Hoffman, Dirk Henrich, and Michael Uppenkamp. "Open-Label Study of Cellular Immunity in Dialysis Patients after Intravenous Ibandronate." Blood 106, no. 11 (November 16, 2005): 3901. http://dx.doi.org/10.1182/blood.v106.11.3901.3901.
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Abstract Intravenous infusion of bisphosphonates can cause acute phase reactions which may be caused by changes in the cellular immune system, particularly in lymphocyte subtypes. These immune changes and an acute phase reaction both normally disappear after 48 hours. Previous studies have shown that kidney transplant recipients treated with immunosuppressive therapy and ibandronate for bone protection have a lower rejection rate than those treated with immunosuppressive therapy and placebo.1 This suggests that there may be long-term changes in the immune system occurring with ibandronate treatment. We investigated the long term changes in the cellular immune system during ibandronate treatment in dialysis patients. As these patients are not normally treated with immunosuppressive or cytotoxic agents, which can cause changes in the cellular immune system, they are an eligible population for such a study. In this open-label trial, 16 patients with end-stage renal disease receiving regular hemodialysis were recruited. All patients were treated with ibandronate 2mg every 4 weeks for renal osteopathy; a dose that provides similar AUC and bone exposure as a 6mg dose in patients with normal renal function. The cellular immune system was investigated before first ibandronate application and the measurement was repeated at weeks 2, 4 and 48. The following parameters were measured by blood count differentiation: leucocytes, granulocytes lymphocytes, monocytes. Lymphocyte subtypes were measured by flow cytometry: B-lymphocytes (CD3+/CD19+), T-helper cells (CD3+/CD4+), T-suppressor cells (CD3+/CD8+), natural killer (NK)-cells (CD3+/CD16+56+), helper-inducer cells (CD4+/CD29+), activated T-cells (CD3+/HLA-DR+), activated T-lymphocytes (CD3+/CD25+), naive T-cells (CD3+/CD45RA+) and memory-T-lymphocytes (CD3+/CD45RO+). Twelve patients completed the study and were evaluated. One patient dropped out because of flu-like symptoms with muscle pain after the first ibandronate infusion; however this was well controlled with paracetamol. Three patients died due to concomitant diseases (diabetes and cardiovascular events). There were no statistically significant differences in cellular immunity over time as measured in weeks 0, 2, 4 and 48 (see Figure). In this small-pilot study of dialysis patients receiving ibandronate, no changes in the cellular immune system were observed over time. Changes in different lymphocyte subtypes, which occur in the acute phase reaction after first infusion, were not seen. Reduced rejection rate in transplant recipients after ibandronate infusion cannot be explained by changes in the cellular immune system, and must therefore occur by another mechanism. Figure Figure
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Huber, S. A., D. Sartini, and M. Exley. "Vγ4+ T Cells Promote Autoimmune CD8+ Cytolytic T-Lymphocyte Activation in Coxsackievirus B3-Induced Myocarditis in Mice: Role for CD4+ Th1 Cells." Journal of Virology 76, no. 21 (November 1, 2002): 10785–90. http://dx.doi.org/10.1128/jvi.76.21.10785-10790.2002.
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ABSTRACT T cells expressing the Vγ4 T-cell receptor (TCR) promote myocarditis in coxsackievirus B3 (CVB3)-infected BALB/c mice. CD1, a major histocompatibility complex (MHC) class I-like molecule, is required for activation of Vγ4+ cells. Once activated, Vγ4+ cells initiate myocarditis through gamma interferon (IFN-γ)-mediated induction of CD4+ T helper type 1 (Th1) cells in the infected animal. These CD4+ Th1 cells are required for activation of an autoimmune CD8+ αβ TCR+ effector, which is the predominant pathogenic agent in this model of CVB3-induced myocarditis. Activated Vγ4+ cells can adoptively transfer myocarditis into BALB/c mice infected with a nonmyocarditic variant of CVB3 (H310A1) but cannot transfer myocarditis into either uninfected or CD1−/− recipients, demonstrating the need for both infection and CD1 expression for Vγ4+ cell function. In contrast, CD8+ αβ TCR+ cells transfer myocarditis into either infected CD1−/− or uninfected recipients, showing that once activated, the CD8+ αβ TCR+ effectors function independently of both virus and CD1. Vγ4+ cells given to mice lacking CD4+ T cells minimally activate the CD8+ αβ TCR+ cells. These studies show that Vγ4+ cells determine CVB3 pathogenicity by their ability to influence both the CD4+ and CD8+ adaptive immune response. Vγ4+ cells enhance CD4+ Th1 (IFN-γ+) cell activation through IFN-γ- and CD1-dependent mechanisms. CD4+ Th1 cells promote activation of the autoimmune CD8+ αβ TCR+ effectors.
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Cho, Sung Hoon, Ariel L. Raybuck, Julianna Blagih, Edna Kemboi, Volker H. Haase, Russell G. Jones, and Mark R. Boothby. "Hypoxia-inducible factors in CD4+ T cells promote metabolism, switch cytokine secretion, and T cell help in humoral immunity." Proceedings of the National Academy of Sciences 116, no. 18 (April 15, 2019): 8975–84. http://dx.doi.org/10.1073/pnas.1811702116.
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T cell help in humoral immunity includes interactions of B cells with activated extrafollicular CD4+ and follicular T helper (Tfh) cells. Each can promote antibody responses but Tfh cells play critical roles during germinal center (GC) reactions. After restimulation of their antigen receptor (TCR) by B cells, helper T cells act on B cells via CD40 ligand and secreted cytokines that guide Ig class switching. Hypoxia is a normal feature of GC, raising questions about molecular mechanisms governing the relationship between hypoxia response mechanisms and T cell help to antibody responses. Hypoxia-inducible factors (HIF) are prominent among mechanisms that mediate cellular responses to limited oxygen but also are induced by lymphocyte activation. We now show that loss of HIF-1α or of both HIF-1α and HIF-2α in CD4+ T cells compromised essential functions in help during antibody responses. HIF-1α depletion from CD4+ T cells reduced frequencies of antigen-specific GC B cells, Tfh cells, and overall antigen-specific Ab after immunization with sheep red blood cells. Compound deficiency of HIF-1α and HIF-2α led to humoral defects after hapten-carrier immunization. Further, HIF promoted CD40L expression while restraining the FoxP3-positive CD4+ cells in the CXCR5+ follicular regulatory population. Glycolysis increases T helper cytokine expression, and HIF promoted glycolysis in T helper cells via TCR or cytokine stimulation, as well as their production of cytokines that direct antibody class switching. Indeed, IFN-γ elaboration by HIF-deficient in vivo-generated Tfh cells was impaired. Collectively, the results indicate that HIF transcription factors are vital components of the mechanisms of help during humoral responses.
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Savaşan, Süreyya, Batool AlQanber, Meret Henry, Steven Buck, and Manisha Gadgeel. "Differing reflections of paediatric classical Hodgkin’s lymphoma on local and distant immunological microenvironments: a flow cytometric study." Journal of Clinical Pathology 73, no. 3 (September 21, 2019): 176–79. http://dx.doi.org/10.1136/jclinpath-2019-205967.
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AimsTo compare immunological microenvironments in local and distant lymphoid tissues in Hodgkin’s lymphoma (HL) in children.MethodsWe have analysed diagnostic bone marrow (BM) samples in 22 and corresponding involved lymph node (LN) in eight and peripheral blood (PB) in eight cases of HL by flow cytometry and sought correlations with clinical features retrospectively.ResultsWhile there were significant differences in lymphocyte compositions of BM and LN tissues, the distribution of lymphocyte subsets mimicked each other in BM and PB. CD8-positive cytotoxic T cells predominate the bone marrow in contrast to CD4-positive helper T cells in LN tissue with corresponding CD4/CD8 ratios (0.85 and 5.3, respectively; p=0.002). Additionally, T-large granular lymphocytes population was much higher in BM in comparison to LN tissue (10.5% vs 4.5%; p=0.036).ConclusionsLocal immunological microenvironment appears to be highly influenced by HL tumour cells and distant site lymphocyte composition reflects immune response to control the neoplastic process.