Journal articles: 'Sequential common gamma chain cytokines'

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Noah, T. L., and S. Becker. "Respiratory syncytial virus-induced cytokine production by a human bronchial epithelial cell line." American Journal of Physiology-Lung Cellular and Molecular Physiology 265, no. 5 (November 1, 1993): L472—L478. http://dx.doi.org/10.1152/ajplung.1993.265.5.l472.

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Respiratory syncytial virus (RSV) is the most common cause of lower respiratory infection in infants and young children, but the pathogenesis of RSV-induced inflammation is not well defined. We hypothesized that in vitro infection of a human bronchial epithelial cell line (BEAS) would induce production of proinflammatory cytokines. BEAS cells were infected with RSV, and cells and supernatants were assayed for cytokine mRNA and protein changes at several time points after infection. Cytokine mRNA in BEAS cells was measured by polymerase chain reaction of reverse-transcribed RNA from whole cell lysates; cytokine levels in supernatants were measured by bioassay or immunoassay. Our results indicated that interleukin-5ay or immunoassay. Our results indicated that interleukin-8 (IL-8) was induced at 4 h after infection (during the eclipse phase of RSV infection) with accumulation of IL-8 in supernatants by 24 h after infection. Increased levels of IL-6 and granulocyte macrophage colony-stimulating factor in supernatants were only detected by 96 h after infection, during the RSV replicative phase. Interferon-alpha and -gamma transcripts were not detectable at any time point. We conclude that the effects of RSV on airway inflammation may be at least partly mediated by sequential production of proinflammatory cytokines in infected airway epithelium.

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Zambidis, Elias T., Bruno Peault, Fred Bunz, and Curt I. Civin. "Embryonic Erythropoiesis and Definitive Hematopoiesis from Human Embryonic Stem Cells Is Regulated by Cytokines Controlling HSC Growth." Blood 104, no. 11 (November 16, 2004): 2777. http://dx.doi.org/10.1182/blood.v104.11.2777.2777.

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Abstract Human embryonic stem cells (hESC) provide an invaluable tool for studying the earliest events in human hematopoietic stem cell (HSC) development. We describe novel protocols for the efficient, step-wise differentiation of hESC to embryonic (primitive) erythroid cells and definitive erythro-myeloid cells from embryoid bodies (EB) in semi-solid and liquid cultures. EB cells were re-cultured in semisolid cultures with a cocktail of hematopoietic growth factors at different time points using a modified EB differentiation protocol, and hematopoietic differentiation was analyzed in vitro. The initiation of hematopoiesis, in this model, begins during the first week of EB differentiation. with the formation of primitive macrophages and CD31+/VE-cadherin+ hemato-endothelial clusters that “bud off” primitive embryonic hemoglobin-expressing erythroblasts and multi-potential blast colonies. These clusters ultimately form organized yolk-sac-like structures which produce a loosely adherent primitive hematopoietic cells. After 7–9 days of EB differentiation (prior to CD45 expression), primitive nucleated erythroblast colonies arise and are characterized by a “brilliant red” hemoglobinization under phase microscopy, positivity for embryonic/fetal hemoglobins by Kleihauer-Betke, qRT-PCR assays for epsilon/zeta/gamma chain expression, and a CD71+/glycophorin A+ phenotype. Simultaneously, discrete blast colonies are also shown to develop into mixed multipotential colonies containing secondary erythro-myeloid blast cells, primitive erythroblasts, and macrophages; suggesting a common progenitor for the discrete embryonic phenotypes observed at this stage. Following this first wave of primitive hematopoiesis, definitive CD45+-expressing colony-forming cells (CFC) can be generated from EB cells differentiated for 10–15 days with the sequential appearance of BFU-E, CFU-E, GM-CFC, and multi-lineage CFC. A kinetic expression analysis using qRT-PCR methods, revealed that the first wave of embryonic hematopoiesis at 6–9 days of EB development directly coincides with expression of SCL/TAL1, AML1, GATA1, and GATA2, while the onset of definitive hematopoiesis at 9–15 days directly correlates with increased EB expression of CD34, CD31, CD41, c-myb, and cdx4. In this model, primitive hematopoiesis in EB cells proceeds in the absence of exogenously added growth factors. However, supplementing EB differentiation cultures with FLT3-ligand, KIT-ligand, and THROMBOPOIETIN (FTK), dramatically enhances the number of primitive erythroblast, and multi-lineage blast CFC, as well as the definitive BFU-E, CFU-E, and multi-potent mixed CFC. The kinetics of colony formation for both primitive and definitive CFC is unaffected by FTK supplementation. Moreover, blast cell colonies from EB cells differentiated in the presence of FTK were more potent than those generated without FTK. These blast colonies differentiate into mixed, multi-lineage CD45+/CD13+/CD41+/CD71+/glycophorin A+-expressing colonies that contain both primitive nucleated embryonic hemoglobin-expressing erythroblasts, and definitive mature beta-globin-expressing erythroid cells, neutrophils, monocytes/macrophages, and megakaryocytic precursors. This hESC model reveals the putative existence of a common human progenitor for both embryonic-type and definitive hematopoietic cells, and that cytokines known to expand/self-renew definitive HSC may potentially regulate this differentiation process.

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Shourian, Mitra, Jean-Christophe Beltra, Benoîte Bourdin, and Hélène Decaluwe. "Common gamma chain cytokines and CD8 T cells in cancer." Seminars in Immunology 42 (April 2019): 101307. http://dx.doi.org/10.1016/j.smim.2019.101307.

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Pulliam, Stephanie R., Roman V. Uzhachenko, Samuel E. Adunyah, and Anil Shanker. "Common gamma chain cytokines in combinatorial immune strategies against cancer." Immunology Letters 169 (January 2016): 61–72. http://dx.doi.org/10.1016/j.imlet.2015.11.007.

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Farhat, Ali M., Adam C. Weiner, Cori Posner, Zoe S. Kim, Brian Orcutt-Jahns, Scott M. Carlson, and Aaron S. Meyer. "Modeling cell-specific dynamics and regulation of the common gamma chain cytokines." Cell Reports 35, no. 4 (April 2021): 109044. http://dx.doi.org/10.1016/j.celrep.2021.109044.

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Querfeld, Christiane, Basem M. William, Lubomir Sokol, Oleg Akilov, Brian Poligone, Jasmine Zain, Yutaka Tagaya, and Nazli Azimi. "Co-Inhibition of IL-2, IL-9 and IL-15 By the Novel Immunomodulator, Bnz-1, Provides Clinical Efficacy in Patients with Refractory Cutaneous T Cell Lymphoma in a Phase 1/2 Clinical Trial." Blood 136, Supplement 1 (November 5, 2020): 37. http://dx.doi.org/10.1182/blood-2020-143135.

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Background: Cutaneous T cell lymphoma is incurable with current standard therapies and there is an urgent need for more effective therapies. BNZ-1 is a pegylated peptide antagonist that binds to the common gamma chain signaling receptor for cytokines IL-2, IL-9 and IL-15. We hypothesized that inhibition of these 3 cytokines could generate a therapeutic benefit to CTCL patients through a multipronged mechanism: 1) IL-2 and IL-15 inhibition blocks cytokine-driven propagation/survival of tumor cells 2) IL-2 and IL-9 inhibition lowers the activity of regulatory T-cells that may impede the anti-lymphoma immune response 3) IL-15 inhibition may provide an additional anti-inflammatory effect Methods: A multicenter, open-label Phase 1/2 study was completed to characterize the safety and efficacy of BNZ-1 (NCT03239392). Refractory patients, who have failed FDA-approved or investigational treatments appropriate for the stage of their disease, with a diagnosis of mycosis fungoides (MF) of any stage or Sézary syndrome (SS) were eligible for this trial. In part I of the study, Pts were enrolled in sequential dose cohorts of 0.5 mg/kg, 1mg/kg, 2 mg/kg, and 4 mg/kg to receive weekly intravenous dose of BNZ-1 to characterize safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity. Thereafter, patients were enrolled on an extension phase for 3 months of weekly dosing of BNZ-1. Patients who achieved a response were eligible for a long-term extension arm. Blood samples were collected to assess the impact of BNZ-1 on PD biomarkers including Treg numbers and activation markers of cytotoxic T lymphocytes using FACS analysis. Results: In the dose ranging part of the study, 15 patients (stages IB and IVB) were enrolled across the 4 dose cohorts. All patients completed the first 4 weeks for safety of the study and 9 enrolled in the 3-month extension period and 3 continued in the long term extension (LTE) period for over a year. BNZ-1 showed activity in all doses as it was determined by early signs of clinical efficacy and PD biomarkers. Subsequently, we selected the 2 mg/kg based on PK/PD relationship and clinical efficacy and expanded to a total of 19 patients. Clinical efficacy was measured by mSWAT and Global Response Score (GRS) as defined previously (Olsen E. et al. 2011). Based on the best response, one patient (5%) achieved a complete response, eleven (58%) patients achieved a partial response (50% reduction over baseline) by the end of the study. 7 patients (37%) showed stable disease during the study period. No disease recurrence was observed during the study period. For those patients who responded to the therapy in the dose ranging part of the study, the mean duration of response was calculated to be 9.2 months. Overall, BNZ-1 was well tolerated and showed no serious treatment-related adverse events in this patient population. Furthermore, PD analysis revealed that BNZ-1 discernibly suppressed the inflammatory nature of CTLs in majority of patients that respond to BNZ-1 treatment as measured by reduction in their mSWAT scores Conclusion: BNZ-1, an IL-2, IL-9, and IL-15 inhibitor, may provide a novel treatment option for CTCL patients who relapsed or were refractory with conventional therapies with a favorable toxicity profile. The multifaceted approach of BNZ-1 leads to direct inhibition of malignant cells, activation of tumor immunity, and suppression of inflammation. Since BNZ-1 showed safety and efficacy in challenging rCTCL patient population, its further development in a phase 3 trial is planned. Disclosures Querfeld: Celgene: Research Funding; MiRagen: Consultancy; Trillium: Consultancy; Helsinn: Consultancy; Stemline: Consultancy; Bioniz: Consultancy; Kyowa Kirin: Consultancy. William:Kyowa Kirin: Consultancy, Honoraria; Dova: Research Funding; Merck: Research Funding; Celgene: Consultancy, Honoraria; Guidepoint Global: Consultancy; Incyte: Research Funding; Seattle Genetics: Research Funding. Sokol:Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Honoraria, Speakers Bureau. Akilov:Trillium: Consultancy; Bioniz: Consultancy. Zain:Seattle Genetics: Research Funding; Mundi Pharma: Research Funding; Kyowa Kirin: Research Funding. Tagaya:Bioniz: Consultancy. Azimi:Bioniz: Current Employment.

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Scanzello, C. R., E. Umoh, T. Miles, H. G. Potter, R. Marx, S. Rodeo, S. R. Goldring, and M. K. Crow. "441 COMMON GAMMA-CHAIN CYTOKINES IN PATIENTS WITH EARLY AND END-STAGE OSTEOARTHRITIS." Osteoarthritis and Cartilage 16 (September 2008): S191—S192. http://dx.doi.org/10.1016/s1063-4584(08)60482-3.

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8

Pahwa, Savita. "Role of common gamma chain utilizing cytokines for immune reconstitution in HIV infection." Immunologic Research 38, no. 1-3 (June 21, 2007): 373–86. http://dx.doi.org/10.1007/s12026-007-0036-9.

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Toe, Jesse G., Marc Pellegrini, and Tak Wah Mak. "Promoting immunity during chronic infection—The therapeutic potential of common gamma-chain cytokines." Molecular Immunology 56, no. 1-2 (November 2013): 38–47. http://dx.doi.org/10.1016/j.molimm.2013.04.008.

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Meazza, Raffaella, Bruno Azzarone, Anna Maria Orengo, and Silvano Ferrini. "Role of Common-Gamma Chain Cytokines in NK Cell Development and Function: Perspectives for Immunotherapy." Journal of Biomedicine and Biotechnology 2011 (2011): 1–16. http://dx.doi.org/10.1155/2011/861920.

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NK cells are components of the innate immunity system and play an important role as a first-line defense mechanism against viral infections and in tumor immune surveillance. Their development and their functional activities are controlled by several factors among which cytokines sharing the usage of the common cytokine-receptor gamma chain play a pivotal role. In particular, IL-2, IL-7, IL-15, and IL-21 are the members of this family predominantly involved in NK cell biology. In this paper, we will address their role in NK cell ontogeny, regulation of functional activities, development of specialized cell subsets, and acquisition of memory-like functions. Finally, the potential application of these cytokines as recombinant molecules to NK cell-based immunotherapy approaches will be discussed.

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Sanjabi, Shomyseh, and Richard A. Flavell. "Interaction between TGF-β and the common gamma chain cytokines during an inflammatory immune response." Cell Cycle 9, no. 3 (February 2010): 428–30. http://dx.doi.org/10.4161/cc.9.3.10728.

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SANTO, JAMES P., RALF KUHN, and Werner Muuller. "Common Cytokine Receptor gamma chain (gammac)-Dependent Cytokines: Understanding in vivo Functions by Gene Targeting." Immunological Reviews 148, no. 1 (December 1995): 19–34. http://dx.doi.org/10.1111/j.1600-065x.1995.tb00091.x.

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Taylor, Harry E., Nina A. Calantone, and Richard T. D’Aquila. "mTOR signaling mediates effects of common gamma-chain cytokines on T cell proliferation and exhaustion." AIDS 32, no. 18 (November 2018): 2847–51. http://dx.doi.org/10.1097/qad.0000000000001997.

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Matthews, DJ, PA Clark, J. Herbert, G. Morgan, RJ Armitage, C. Kinnon, A. Minty, KH Grabstein, D. Caput, and P. Ferrara. "Function of the interleukin-2 (IL-2) receptor gamma-chain in biologic responses of X-linked severe combined immunodeficient B cells to IL-2, IL-4, IL-13, and IL-15." Blood 85, no. 1 (January 1, 1995): 38–42. http://dx.doi.org/10.1182/blood.v85.1.38.bloodjournal85138.

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The interleukin-2 (IL-2) receptor gamma-chain is a common component of several members of the cytokine receptor superfamily including those for IL-2, IL-4, IL-7, IL-9, IL-15, and possibly IL-13, and has recently been renamed the common gamma-chain (gamma c-chain). Transfection experiments have shown that the gamma c-chain participates in signal transduction by IL-2, IL-4 and IL-7, but a functional role for the gamma c-chain in biological responses by normal T cells and B cells to these cytokines has not been established. In this study, we have used X- linked severe combined immunodeficiency (X-SCID) as a naturally occurring gamma c-chain gene disruption model to examine the role of the gamma c-chain in human B-cell responses to IL-2, IL-4, IL-13, and IL-15. Our experiments show that B cells from two X-SCID patients with characterized gamma c-chain gene mutations do not respond to IL-2 or IL- 15, but respond as well or better than normal B cells to both IL-4 and IL-13 in assays for B-cell activation, proliferation, and IgE secretion. This finding raises important questions about the function of the gamma c-chain in receptors for IL-4 and IL-13, and the nature of the immune defect in X-SCID.

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Leonard, W. J. "Cytokines that share the common cytokine receptor gamma chain: old ideas and new lessons (LL2-1)." International Immunology 22, Suppl_1_Pt_2 (August 2010): ii7. http://dx.doi.org/10.1093/intimm/dxq089.

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McNamara, Michael J., Melissa J. Kasiewicz, Stefanie N. Linch, Christopher Dubay, and William L. Redmond. "Common gamma chain (¿c) cytokines differentially potentiate TNFR family signaling in antigen-activated CD8 + T cells." Journal for ImmunoTherapy of Cancer 2, no. 1 (2014): 28. http://dx.doi.org/10.1186/preaccept-1295181861132210.

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Schwarze, Vincent, Anne-Kathrin Hechinger, Franziska Leonhardt, Gabriele Prinz, Annette Schmitt-Gräff, Jiri Kovarik, and Robert Zeiser. "Common Gamma Chain Cytokines Contribute To Acute GvHD Via Perforin/Granzyme B-Mediated Cytotoxicity Of CD8 T Cells." Blood 122, no. 21 (November 15, 2013): 2015. http://dx.doi.org/10.1182/blood.v122.21.2015.2015.

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Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is an important treatment option for different hematological malignancies, but also for some nonmalignant hematological disorders such as sickle cell anemia, aplastic anemia or thalassemia(1). In the ladder group the graft-versus-leukemia (GvL) effect mediated by donor T cells is less important and prevention of graft-versus-host disease (GvHD), which occurs in 40-50% of allo-HCT patients, is a major priority. The common gamma chain (CD132) is a cytokine receptor sub-unit that is common to the interleukin (IL) receptors of IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Since several of these cytokines were shown to be increased in the serum of patients developing acute GvHD, we reasoned that inhibition of CD132 could have a profound effect on acute GvHD by inhibiting the bioactivity of multiple proinflammatory cytokines. We observed that anti-CD132 treatment reduced GvHD potently with respect to survival, production of TNF, IFN-γ, IL-6, MCP-1 and GvHD histopathology. Protection was only seen when anti-CD132 was applied in a CD8 T cell-dependent GvHD model while no protection was seen when only CD4 T cells were given. Mechanistically, we could show that CD8 T cells isolated from mice treated with anti-CD132 had reduced levels of Granzyme B and that GvHD induced by Perforin-deficient T cells was resistant towards blockade by anti-CD132 treatment. These data indicated a role of the common gamma chain cytokines for the induction of Perforin/Granzyme B in CD8 T cells during GvHD. Compatible with this notion, exposure of CD8 T cells towards IL-2, IL-7, IL-15 and IL-21 alone or in combination induced increased levels of Granzyme B. Based on these findings, we concluded that CD8 T cells that are activated by common gamma chain cytokines during GvHD produce then Granzyme B which can be blocked by anti-CD132 treatment. This therapeutic approach has particular clinical potential for patients undergoing allogeneic transplantation for nonmalignant indications, since graft-versus-tumor activity is not required. Disclosures: No relevant conflicts of interest to declare.

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Yu, Yuming, Jennifer R. Zitzner, Josetta Houlihan, Nancy Herrera, Luting Xu, Joshua Miller, James M. Mathew, Anat R. Tambur, and Xunrong Luo. "Common Gamma Chain Cytokines Promote Rapid In Vitro Expansion of Allo-Specific Human CD8+ Suppressor T Cells." PLoS ONE 6, no. 12 (December 14, 2011): e28948. http://dx.doi.org/10.1371/journal.pone.0028948.

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Long, S. Alice, Megan Van Landeghen, and Jane Buckner. "Rapamycin Promotes Induction of CD4+Foxp3+ T Cells that Proliferate in Response to Common Gamma Chain Cytokines." Clinical Immunology 123 (2007): S6. http://dx.doi.org/10.1016/j.clim.2007.03.188.

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Van Acker, Heleen H., Diana Campillo-Davo, Gils Roex, Maarten Versteven, Evelien L. Smits, and Viggo F. Van Tendeloo. "The role of the common gamma-chain family cytokines in γδ T cell-based anti-cancer immunotherapy." Cytokine & Growth Factor Reviews 41 (June 2018): 54–64. http://dx.doi.org/10.1016/j.cytogfr.2018.05.002.

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Timofeeva, Sofia V., Anastasia O. Sitkovskaya, Elena Yu Zlatnik, Svetlana Yu Filippova, Tatiana V. Shamova, Irina V. Mezhevova, Inna A. Novikova, et al. "The common gamma-chain cytokines IL-2, IL-7 and IL-15 impact on proliferation of lymphocytes in vitro in breast cancer patients." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e13060-e13060. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e13060.

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e13060 Background: Monotherapy with low doses of cytokines does not provide significant therapeutic results, while treatment with high doses leads to a number of side effects, for example, cytokine release syndrome, etc. Therefore, it is necessary to study the effect of cytokines on immune cells which are involved in the regulation of pro- and antitumor immune response. Thus, the aim of this study was to analyze the dynamics in the proliferation of the total fraction of lymphocytes after expansion and exposure to γc-cytokines: IL-2, IL-7 and IL-15 and their combinations in vitro in patients with diagnosed breast cancer. Methods: The study included 10 patients with locally advanced stage I-III breast cancer. Peripheral blood mononuclear cells (PBMC, ficoll-hypaque) were used as material. After density separation the cells were cultured at a dose of 500 thousand cells / ml in 6-well plates (Biofil, China) in RPMI 1640 (Gibco, USA) supplemented with 10% FBS (HyClone, USA) at 37° C, 5% CO2. Expansion of lymphocytes was performed by kit with anti-biotin magnetic particles MACSiBead to CD2, CD3 and CD28 (Miltenyi Biotec, Germany), according to the manufacturer's protocol. Stimulation of lymphocyte proliferation was performed on days 4, 8 and 12 by introducing recombinant cytokines - IL-2, IL-7, IL-15 (Miltenyi Biotec, Germany) and their combinations. Cytokines were introduced at a concentration of 40 ng / ml each in the following variants: IL-2; IL-2 / IL-15; IL-2 / IL-15 / IL-7; IL-15; IL-15 / IL-7. Plates with cell suspension were cultured at 37 ° C, 5% CO2 for 15 days. Results: The data obtained on the 11th day of incubation demonstrated statistically significant differences in cell viability in samples with the addition of interleukin IL-7 / IL-15 combination (778%) compared to control samples by 1.5 times (p < 0.05). The proportion of lymphocytes in samples with the addition of only IL-15 (702%) and IL-7 / IL-15 (756%) combination was 1.47 and 1.6 times higher, respectively, compared with the control (p < 0.05) at the 12th day of co-cultivation. Conclusions: Stimulation of lymphocyte proliferation by the IL-7 / IL-15 combination results in a high frequency of viable cell production. Despite the only culture stage, the results of the study may be important for optimizing the use of γc-cytokines in the treatment of patients with breast cancer.

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Myklebust, June H., Jonathan M. Irish, Roch Houot, Joshua Brody, Debra K. Czerwinski, Ash A. Alizadeh, Arne Kolstad, and Ronald Levy. "A Subpopulation of Follicular Lymphoma Tumor Infiltrating T Cells Shows Suppressed Common Gamma Chain Cytokine Signaling." Blood 114, no. 22 (November 20, 2009): 759. http://dx.doi.org/10.1182/blood.v114.22.759.759.

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Abstract Abstract 759 Introduction: Tumor infiltrating T cells present within biopsy specimens of human B cell non-Hodgkin's lymphomas (NHL) provide a valuable opportunity to examine immune system function in the presence of cancer. We recently used flow cytometry to characterize signaling in subpopulations of tumor samples from patients with follicular lymphoma (FL). In FL, we identified a novel lymphoma cell subset with impaired B cell antigen receptor (BCR) signaling, the prevalence of which correlated with adverse clinical outcome. Here, we turned our attention to signaling differences in subsets of the tumor-infiltrating T cells from FL and two other NHLs, diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Signaling differences that distinguish the tumor infiltrating T cells from each malignancy might be expected to be a reflection of the specific disease microenvironment, whereas T cell signaling differences distinguishing cases of the same malignancy might be related to the biology of each patient's tumor. Methods: Single cell flow cytometry measurements of signaling were acquired for samples of DLBCL (N=13), MCL (N=20), and FL (N=14). Phosphorylation of 14 signaling proteins was measured under 12 stimulation conditions in every cell, including lymphoma B cells and tumor-infiltrating T cells within the same specimen. Stimulation conditions included those that were B cell specific (BCR crosslinking, CD40 ligand), T cell specific (IL-7), and those that stimulated both B and T cells (IL-4, IL-10, IL-21, PMA + ionomycin, and IFN-γ). Results: Striking differences were observed in the signaling responses of tumor infiltrating T cells. T cells infiltrating FL patient samples showed significantly lower responses to cytokines where signal transduction is mediated by the common γ chain receptor. Specifically, we observed significant lower induction of p-STAT6 after IL-4 stimulation, p-STAT5 after IL-7 stimulation, and p-STAT3 after IL-21 stimulation (p < 0.001 for FL vs. MCL in all cases). In contrast, receptor-independent signaling was not significantly different as FL tumor infiltrating T cells responded at a level comparable to MCL and DLBCL tumor infiltrating T cells when stimulated with PMA and ionomycin. The lower response to common γ chain family cytokines could be the result of a partial suppression of all tumor infiltrating T cells or a complete suppression of a distinct subset. To distinguish between these possibilities, we analyzed signaling in tumor infiltrating T cell subsets. This single cell approach showed that tumor infiltrating T cells were a heterogeneous mixture of non-responsive cells and highly responsive T cells in response to cytokines. Specifically, the mean percentage of T cells that did not induce p-STAT3 after IL-21 stimulation was 50.3% in FL samples in contrast to only 26.2% in MCL samples. Phenotypic analysis showed that the vast majority of T cells infiltrating FL patient samples were CD4+CD45RO memory cells, and the single cell signaling approach revealed that the FL nonresponsive T cell subset had this phenotype. Furthermore, FL T cells were composed of a significantly larger fraction of T regulatory cells than MCL T cells, on average 17% FoxP3+CD25+ cells compared to only 9% in MCL (p<0.0002). Experiments are ongoing to test whether the prevalence of T regulatory cells influence the signaling capacity of the remaining CD4 conventional T cells. Conclusions: A subpopulation of tumor infiltrating T cells within FL patient samples has reduced responsiveness to the common gamma chain family members IL-4, IL-7 and IL-21, and distinguishes FL from DLBCL and MCL. These results may reflect a more suppressive microenvironment in FL. Disclosures: No relevant conflicts of interest to declare.

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Le Floc’h, Audrey, Kirsten Nagashima, Thomas Norton, Lorah Perlee, Andrew Murphy, Matthew Sleeman, and Jamie Orengo. "Blockade of Common Gamma Chain Cytokines with REGN7257, an Interleukin 2 Receptor Gamma (IL2RG) Monoclonal Antibody, Protected Mice from Graft-Versus-Host Disease." Transplantation and Cellular Therapy 27, no. 3 (March 2021): S250—S251. http://dx.doi.org/10.1016/s2666-6367(21)00314-6.

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Beltra, Jean-Christophe, Sara Bourbonnais, Nathalie Bédard, Tania Charpentier, Moana Boulangé, Eva Michaud, Ines Boufaied, et al. "IL2Rβ-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection." Proceedings of the National Academy of Sciences 113, no. 37 (August 29, 2016): E5444—E5453. http://dx.doi.org/10.1073/pnas.1604256113.

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Exhaustion of CD8+ T cells severely impedes the adaptive immune response to chronic viral infections. Despite major advances in our understanding of the molecular regulation of exhaustion, the cytokines that directly control this process during chronicity remain unknown. We demonstrate a direct impact of IL-2 and IL-15, two common gamma-chain–dependent cytokines, on CD8+ T-cell exhaustion. Common to both cytokine receptors, the IL-2 receptor β (IL2Rβ) chain is selectively maintained on CD8+ T cells during chronic lymphocytic choriomeningitis virus and hepatitis C virus infections. Its expression correlates with exhaustion severity and identifies terminally exhausted CD8+ T cells both in mice and humans. Genetic ablation of the IL2Rβ chain on CD8+ T cells restrains inhibitory receptor induction, in particular 2B4 and Tim-3; precludes terminal differentiation of highly defective PD-1hi effectors; and rescues memory T-cell development and responsiveness to IL-7–dependent signals. Together, we ascribe a previously unexpected role to IL-2 and IL-15 as instigators of CD8+ T-cell exhaustion during chronic viral infection.

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Massoud, Raya, Yoshimi Enose-Akahata, Yutaka Tagaya, Nazli Azimi, Asjad Basheer, and Steven Jacobson. "Common γ-chain blocking peptide reduces in vitro immune activation markers in HTLV-1-associated myelopathy/tropical spastic paraparesis." Proceedings of the National Academy of Sciences 112, no. 35 (August 17, 2015): 11030–35. http://dx.doi.org/10.1073/pnas.1412626112.

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Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive inflammatory myelopathy occurring in a subset of HTLV-1-infected individuals. Despite advances in understanding its immunopathogenesis, an effective treatment remains to be found. IL-2 and IL-15, members of the gamma chain (γc) family of cytokines, are prominently deregulated in HAM/TSP and underlie many of the characteristic immune abnormalities, such as spontaneous lymphocyte proliferation (SP), increased STAT5 phosphorylation in the lymphocytes, and increased frequency and cytotoxicity of virus-specific cytotoxic CD8+ T lymphocytes (CTLs). In this study, we describe a novel immunomodulatory strategy consisting of selective blockade of certain γc family cytokines, including IL-2 and IL-15, with a γc antagonistic peptide. In vitro, a PEGylated form of the peptide, named BNZ132-1-40, reduced multiple immune activation markers such as SP, STAT5 phosphorylation, spontaneous degranulation of CD8+ T cells, and the frequency of transactivator protein (Tax)-specific CD8+ CTLs, thought to be major players in the immunopathogenesis of the disease. This strategy is thus a promising therapeutic approach to HAM/TSP with the potential of being more effective than single monoclonal antibodies targeting either IL-2 or IL-15 receptors and safer than inhibitors of downstream signaling molecules such as JAK1 inhibitors. Finally, selective cytokine blockade with antagonistic peptides might be applicable to multiple other conditions in which cytokines are pathogenic.

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Ganbold, Anar, Sean Andersen, Szun S. Tay, Eithne Cunningham, Victor Ilie, Sai Krishnan, Chuanmin Wang, Geoffrey W. McCaughan, Alexandra F. Sharland, and G. Alex Bishop. "Expression of common gamma chain signalling cytokines and their receptors distinguishes rejection from tolerance in a rat organ transplant model." Transplant Immunology 27, no. 2-3 (October 2012): 89–94. http://dx.doi.org/10.1016/j.trim.2012.08.001.

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Vanhanen, Reetta, Anni Tuulasvaara, Joonatan Mattila, Tommi Pätilä, and T. Petteri Arstila. "Common gamma chain cytokines promote regulatory T cell development and survival at the CD4+ CD8+ stage in the human thymus." Scandinavian Journal of Immunology 88, no. 2 (July 20, 2018): e12681. http://dx.doi.org/10.1111/sji.12681.

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28

Cornish, Georgina H., Linda V. Sinclair, and Doreen A. Cantrell. "Differential regulation of T-cell growth by IL-2 and IL-15." Blood 108, no. 2 (July 15, 2006): 600–608. http://dx.doi.org/10.1182/blood-2005-12-4827.

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Although interleukin 2 (IL-2) and IL-15 signal through the common gamma chain (γc) and through IL-2 receptor β–chain (CD122) subunits, they direct distinct physiologic and immunotherapeutic responses in T cells. The present study provides some insight into why IL-2 and IL-15 differentially regulate T-cell function by revealing that these cytokines are strikingly distinct in their ability to control protein synthesis and T-cell mass. IL-2 and IL-15 are shown to be equivalent mitogens for antigen-stimulated CD8+ T cells but not for equivalent growth factors. Antigen-primed T cells cannot autonomously maintain amino acid incorporation or de novo protein synthesis without exogenous cytokine stimulation. Both IL-2 and IL-15 induce amino acid uptake and protein synthesis in antigen-activated T cells; however, the IL-2 response is strikingly more potent than the IL-15 response. The differential action of IL-2 and IL-15 on amino acid uptake and protein synthesis is explained by temporal differences in signaling induced by these 2 cytokines. Hence, the present results show that cytokines that are equivalent mitogens can have different potency in terms of regulating protein synthesis and cell growth.

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Santo, James P., Francesco Colucci, and Delphine Guy-Grand. "Natural killer and T cells of innate and adaptive immunity: lymphoid compartments with different requirements for common gamma chain-dependent cytokines." Immunological Reviews 165, no. 1 (October 1998): 29–38. http://dx.doi.org/10.1111/j.1600-065x.1998.tb01227.x.

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30

Musso, T., J. A. Johnston, D. Linnekin, L. Varesio, T. K. Rowe, J. J. O'Shea, and D. W. McVicar. "Regulation of JAK3 expression in human monocytes: phosphorylation in response to interleukins 2, 4, and 7." Journal of Experimental Medicine 181, no. 4 (April 1, 1995): 1425–31. http://dx.doi.org/10.1084/jem.181.4.1425.

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The Janus family of kinases (JAKs) has been shown to be involved in the signal transduction of a number of cytokine receptors. Recently, we have cloned a novel JAK family member, JAK3, that is expressed in natural killer and activated T cells and is coupled functionally and physically to the interleukin 2 (IL-2) receptor in these cells. Here we report that JAK3 was expressed at low but detectable levels in human monocytes. In contrast, JAK3 expression was strongly induced during activation by interferon gamma (IFN-gamma) or lipopolysaccharide. Moreover, JAK3 became tyrosine phosphorylated in response to IL-2, IL-4, and IL-7 but not response to IFN-gamma or granulocyte/macrophage colony-stimulating factor. Together, these findings suggest that JAK3 is functionally important in activated monocytes and cells of the myeloid lineage and is involved in signaling responses of cytokines that use the common gamma-chain of the IL-2 receptor.

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31

Trinité, Benjamin, Chi N. Chan, Caroline S. Lee, and David N. Levy. "HIV-1 Vpr- and Reverse Transcription-Induced Apoptosis in Resting Peripheral Blood CD4 T Cells and Protection by Common Gamma-Chain Cytokines." Journal of Virology 90, no. 2 (November 4, 2015): 904–16. http://dx.doi.org/10.1128/jvi.01770-15.

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ABSTRACTHIV-1 infection leads to the progressive depletion of the CD4 T cell compartment by various known and unknown mechanisms.In vivo, HIV-1 infects both activated and resting CD4 T cells, butin vitro, in the absence of any stimuli, resting CD4 T cells from peripheral blood are resistant to infection. This resistance is generally attributed to an intracellular environment that does not efficiently support processes such as reverse transcription (RT), resulting in abortive infection. Here, we show thatin vitroHIV-1 infection of resting CD4 T cells induces substantial cell death, leading to abortive infection.In vivo, however, various microenvironmental stimuli in lymphoid and mucosal tissues provide support for HIV-1 replication. For example, common gamma-chain cytokines (CGCC), such as interleukin-7 (IL-7), render resting CD4 T cells permissible to HIV-1 infection without inducing T cell activation. Here, we find that CGCC primarily allow productive infection by preventing HIV-1 triggering of apoptosis, as evidenced by early release of cytochromecand caspase 3/7 activation. Cell death is triggered both by products of reverse transcription and by virion-borne Vpr protein, and CGCC block both mechanisms. When HIV-1 RT efficiency was enhanced by SIVmac239 Vpx protein, cell death was still observed, indicating that the speed of reverse transcription and the efficiency of its completion contributed little to HIV-1-induced cell death in this system. These results show that a major restriction on HIV-1 infection in resting CD4 T cells resides in the capacity of these cells to survive the early steps of HIV-1 infection.IMPORTANCEA major consequence of HIV-1 infection is the destruction of CD4 T cells. Here, we show that delivery of virion-associated Vpr protein and the process of reverse transcription are each sufficient to trigger apoptosis of resting CD4 T cells isolated from peripheral blood. While these 2 mechanisms have been previously described in various cell types, we show for the first time their concerted effect in inducing resting CD4 T cell depletion. Importantly, we found that cytokines such as IL-7 and IL-4, which are particularly active in sites of HIV-1 replication, protect resting CD4 T cells from these cytopathic effects and, primarily through this protection, rather than through enhancement of specific replicative steps, they promote productive infection. This study provides important new insights for the understanding of the early steps of HIV-1 infection and T cell depletion.

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Schena, F. P., L. Gesualdo, and V. Montinaro. "Immunopathological aspects of immunoglobulin A nephropathy and other mesangial proliferative glomerulonephritides." Journal of the American Society of Nephrology 2, no. 10 (April 1992): S167. http://dx.doi.org/10.1681/asn.v210s167.

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Immunoglobulin A nephropathy (IgAN) is an immune complex (IC) glomerulonephritis (GN) that represents one of the most common forms of primary glomerular disease. Proliferation of mesangial cells and the increase of mesangial matrix are histological hallmarks of mesangioproliferative GN. Increased serum levels of IgA, polymeric IgA, IgA rheumatoid factor, IgA-IC, and spontaneous or pokeweed mitogen-induced production of IgA by peripheral blood mononuclear cells are major humoral immune alterations reported in IgAN. Recently, we focused on the role of cytokines and growth factors in the mediation of glomerular injury. Platelet-derived growth factor, transforming growth factor beta, interleukin (IL)-1 and IL-6 are expressed by and act on mesangial cells. Increased expression of platelet-derived growth factor was found in both an active model of IgAN and in renal biopsies of patients with proliferative GN. A strict correlation between increased expression of B-chain mRNA and mesangial proliferation was found. Cytokines such as IL-1, interferon gamma, and IL-6, released by infiltrating mononuclear cells or produced locally by mesangial cells, affect the glomerular response to IgA-IC. In a passive murine experimental model of IgAN, IL-1 and interferon gamma increased mesangial hypercellularity, whereas IL-6 was highly pathogenic when associated to IL-1. In conclusion, classical immunological mechanisms in mesangial GN could interact with other pathways involving cytokines and growth factors in the progression of glomerular injury.

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33

Koenderman, L., SW Hermans, PJ Capel, and JG van de Winkel. "Granulocyte-macrophage colony-stimulating factor induces sequential activation and deactivation of binding via a low-affinity IgG Fc receptor, hFc gamma RII, on human eosinophils." Blood 81, no. 9 (May 1, 1993): 2413–19. http://dx.doi.org/10.1182/blood.v81.9.2413.2413.

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Abstract Eosinophils are important in antibody-mediated immune defense against parasites based on interaction with Ig receptors (FcR). Of the three classes of IgG FcR in humans, hFc gamma RI, II, and III, solely hFc gamma RII (CD32) is expressed on freshly isolated eosinophils. Despite an expression level similar to that found on monocytes and polymorphonuclear granulocytes, binding activity of hFc gamma RII on eosinophils is constitutively low. Freshly isolated eosinophils had a negligible ability to form rosettes with IgG-sensitized erythrocytes (EA-IgG). Addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) caused an approximately threefold increase in EA-IgG rosettes. This increase was maximal after 35 minutes, and declined upon further incubation at 37 degrees C. Analysis of hFc gamma RII expression levels showed no significant changes and neither was the expression of other hFc gamma R classes induced. Blocking studies with anti-Fc gamma receptor monoclonal antibody (MoAb) proved hFc gamma RII specificity of enhanced IgG complex binding. These phenomena were not restricted to GM- CSF action, because the addition of interleukin-3 or interleukin-5 similarly enhanced EA-IgG binding. The kinetics of activation of hFc gamma RII binding activity were paralleled by the binding of EA-C3bi to CR3 on eosinophils. In contrast to the stable expression of hFc gamma RII during activation with GM-CSF, CR3 expression increased slowly. Ligand binding via both types of opsonin receptors proved receptor specific. However, the kinetics of enhanced binding via hFc gamma RII and CR3 suggested the possibility of a common mechanism underlying the enhancement of ligand binding via hFc gamma RII and CR3. This hypothesis was supported by the fact that binding via hFc gamma RII proved sensitive to both high concentrations of F(ab')2 fragments of anti-CD11b MoAb MO1 and chelation of bivalent cations with EDTA. In conclusion, our studies indicate that cytokines can induce a transient enhancement of hFc gamma RII binding activity. Qualitative, and not quantitative, changes in this receptor appear to underly the modulation of binding activity, which may be linked to changes in CR3 activity.

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34

Koenderman, L., SW Hermans, PJ Capel, and JG van de Winkel. "Granulocyte-macrophage colony-stimulating factor induces sequential activation and deactivation of binding via a low-affinity IgG Fc receptor, hFc gamma RII, on human eosinophils." Blood 81, no. 9 (May 1, 1993): 2413–19. http://dx.doi.org/10.1182/blood.v81.9.2413.bloodjournal8192413.

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Eosinophils are important in antibody-mediated immune defense against parasites based on interaction with Ig receptors (FcR). Of the three classes of IgG FcR in humans, hFc gamma RI, II, and III, solely hFc gamma RII (CD32) is expressed on freshly isolated eosinophils. Despite an expression level similar to that found on monocytes and polymorphonuclear granulocytes, binding activity of hFc gamma RII on eosinophils is constitutively low. Freshly isolated eosinophils had a negligible ability to form rosettes with IgG-sensitized erythrocytes (EA-IgG). Addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) caused an approximately threefold increase in EA-IgG rosettes. This increase was maximal after 35 minutes, and declined upon further incubation at 37 degrees C. Analysis of hFc gamma RII expression levels showed no significant changes and neither was the expression of other hFc gamma R classes induced. Blocking studies with anti-Fc gamma receptor monoclonal antibody (MoAb) proved hFc gamma RII specificity of enhanced IgG complex binding. These phenomena were not restricted to GM- CSF action, because the addition of interleukin-3 or interleukin-5 similarly enhanced EA-IgG binding. The kinetics of activation of hFc gamma RII binding activity were paralleled by the binding of EA-C3bi to CR3 on eosinophils. In contrast to the stable expression of hFc gamma RII during activation with GM-CSF, CR3 expression increased slowly. Ligand binding via both types of opsonin receptors proved receptor specific. However, the kinetics of enhanced binding via hFc gamma RII and CR3 suggested the possibility of a common mechanism underlying the enhancement of ligand binding via hFc gamma RII and CR3. This hypothesis was supported by the fact that binding via hFc gamma RII proved sensitive to both high concentrations of F(ab')2 fragments of anti-CD11b MoAb MO1 and chelation of bivalent cations with EDTA. In conclusion, our studies indicate that cytokines can induce a transient enhancement of hFc gamma RII binding activity. Qualitative, and not quantitative, changes in this receptor appear to underly the modulation of binding activity, which may be linked to changes in CR3 activity.

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35

Meißner, Udo, Horst Blum, Markus Schnare, Martin Röllinghoff, and André Gessner. "A soluble form of the murine common γ chain is present at high concentrations in vivo and suppresses cytokine signaling." Blood 97, no. 1 (January 1, 2001): 183–91. http://dx.doi.org/10.1182/blood.v97.1.183.

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Abstract The common gamma-chain (γc) is a component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 and is essential for their signal transduction. Western blotting and a newly established enzyme-linked immunosorbent assay detected substantial constitutive levels (50-250 ng/mL) of soluble γc (sγc) in sera of murine inbred strains. It was demonstrated that purified immune cells, such as T, B, and natural killer cells, and macrophages released this protein after activation. Transfection experiments with cDNA encoding the full-length γc showed that shedding of the transmembrane receptor led to the release of sγc. The shedding enzymes, however, appeared to be distinct from those cleaving other cytokine receptors because inhibitors of metalloproteases (eg, TAPI) did not influence sγc release. In vivo, superantigen-induced stimulation of T cells enhanced sγc serum concentrations up to 10-fold within 6 hours. Because these findings demonstrated regulated expression of a yet unknown molecule in the immune response, further experiments were performed to assess the possible function(s) of sγc. A physiological role of sγc was indicated by its capacity to specifically inhibit cell growth induced by γc-dependent cytokines. Mutational analysis revealed that the C-terminus and the WSKWS motif are essential for the cytokine inhibitory effect of the sγc and for binding of the molecule to cytokine receptor-expressing cells. Thus, competitive displacement of the transmembrane γc by excess sγc is the most likely mechanism of cell growth inhibition. It was implied that naturally produced sγc is a negative modulator of γc-dependent cytokines.

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36

Schnyder, B., S. Lugli, N. Feng, H. Etter, RA Lutz, B. Ryffel, K. Sugamura, H. Wunderli- Allenspach, and R. Moser. "Interleukin-4 (IL-4) and IL-13 bind to a shared heterodimeric complex on endothelial cells mediating vascular cell adhesion molecule-1 induction in the absence of the common gamma chain." Blood 87, no. 10 (May 15, 1996): 4286–95. http://dx.doi.org/10.1182/blood.v87.10.4286.bloodjournal87104286.

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Interleukin-4 (IL-4) and IL-13 exert similar, nonadditive effects on endothelial cells, inducing vascular cell adhesion molecule-1 (VCAM-1) expression and subsequent transmigration of eosinophils. The receptor for IL-4 and IL-13 was described as a shared heteromultimeric complex in which the common gamma-chain (gamma c) subunit was essential for activity. Endothelial cell bound both cytokines with high affinity; by flow cytofluorometry and reverse transcription-polymerase chain reaction (RT-PCR), they expressed IL-4 receptor alpha (IL-4R alpha) but did not express the gamma c of the IL-2R. Radioligand cross-linking experiments followed by immunoprecipitation with the monoclonal antibody (MoAb) S697 to the IL-4R alpha showed IL-4-specific binding at 130 kD, the IL-4R alpha, and to a minor extent to a double band coimmunoprecipitated at 65 to 75 kD. [125 I]IL-13 bound predominantly to the 65- to 75- kD band and with a trace amount of binding at 130 kD. However, no ligand-cross-linked receptor was precipitated by the MoAb S697, indicating a cognate novel IL-13-binding subunit. Excess unlabeled IL-4 completely displaced IL-13 binding. Similarly, nonsignaling IL-4 (Y124D)-mutant abolished IL-4- and IL-13-mediated signal transduction. Unlabeled IL-13 competed successfully for IL-4 binding at 65 to 75 kD but was unable to completely displace Il-4 from its binding to the IL-4R alpha. The MoAb TUGh4, specific for the gamma c, failed to precipitate ligand-cross-linked IL-4R and IL-13R. Therefore, the subunit structure of the functional receptors for IL-4 and IL-13 on human endothelial cells does not use or require the common gamma c of the IL-2R.

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37

KAY, THOMAS, GAURANG JHALA, BALASUBRAMANIAN KRISHNAMURTHY, and HELEN E. THOMAS. "290-OR: Diabetes Progression in IFG-Receptor Deficient NOD Mice Is Associated with Increased CD8+ T Lymphocyte Sensitivity to Common Gamma Chain Cytokines." Diabetes 69, Supplement 1 (June 2020): 290—OR. http://dx.doi.org/10.2337/db20-290-or.

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38

Kopf, Manfred, Luigi Tortola, Iwana Schmitz, Anja Fröhlich, Ivo Sonderegger, Helga Pawelski, and Christoph Schneider. "Orchestration of B and T cell responses in health and disease by common gamma chain family cytokines with a focus on IL-21." Arthritis Research & Therapy 13, Suppl 2 (2011): O9. http://dx.doi.org/10.1186/ar3413.

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39

von Holzen, Urs, Michel Adamina, Martin Bolli, Walter P. Weber, Paul Zajac, Celia Groeper, Anca Reschner, et al. "Selective responsiveness to common gamma chain cytokines in peripheral blood-derived cytotoxic T lymphocytes induced by Melan-A/MART-127-35targeted active specific immunotherapy." International Journal of Cancer 115, no. 2 (2005): 248–55. http://dx.doi.org/10.1002/ijc.20858.

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40

Whitwam, Todd, Mark E. Haskins, Paula S. Henthorn, Jennifer N. Kraszewski, Sandra E. Kleiman, Nancy E. Seidel, David M. Bodine, and Jennifer M. Puck. "Retroviral Marking of Canine Bone Marrow: Long-Term, High-Level Expression of Human Interleukin-2 Receptor Common Gamma Chain in Canine Lymphocytes." Blood 92, no. 5 (September 1, 1998): 1565–75. http://dx.doi.org/10.1182/blood.v92.5.1565.

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Abstract Optimization of retroviral gene transfer into hematopoietic cells of the dog will facilitate gene therapy of canine X-linked severe combined immunodeficiency (XSCID) and in turn advance similar efforts to treat human XSCID. Both canine and human XSCID are caused by defects in the common γ chain, γc, of receptors for interleukin-2 and other cytokines. In this study, normal dogs were given retrovirally transduced bone marrow cells with and without preharvest mobilization by the canine growth factors granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF). Harvey sarcoma virus and Moloney murine leukemia virus constructs were used, both containing cDNA encoding human γc. The Harvey-based vector transduced into cytokine-primed marrow yielded persistent detectable provirus in bone marrow and blood and expression of human γc on peripheral lymphocytes. In three dogs, human γc expression disappeared after 19 to 34 weeks but reappeared and was sustained, in one dog beyond 16 months posttransplantation, upon immunosuppression with cyclosporin A and prednisone, with up to 25% of lymphocytes expressing human γc. The long-term expression of human γc in a high proportion of normal canine lymphocytes predicts that retrovirus-mediated gene correction of hematopoietic cells may prove to be of clinical benefit in humans affected with this XSCID. This is a US government work. There are no restrictions on its use.

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41

Whitwam, Todd, Mark E. Haskins, Paula S. Henthorn, Jennifer N. Kraszewski, Sandra E. Kleiman, Nancy E. Seidel, David M. Bodine, and Jennifer M. Puck. "Retroviral Marking of Canine Bone Marrow: Long-Term, High-Level Expression of Human Interleukin-2 Receptor Common Gamma Chain in Canine Lymphocytes." Blood 92, no. 5 (September 1, 1998): 1565–75. http://dx.doi.org/10.1182/blood.v92.5.1565.417k12_1565_1575.

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Optimization of retroviral gene transfer into hematopoietic cells of the dog will facilitate gene therapy of canine X-linked severe combined immunodeficiency (XSCID) and in turn advance similar efforts to treat human XSCID. Both canine and human XSCID are caused by defects in the common γ chain, γc, of receptors for interleukin-2 and other cytokines. In this study, normal dogs were given retrovirally transduced bone marrow cells with and without preharvest mobilization by the canine growth factors granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF). Harvey sarcoma virus and Moloney murine leukemia virus constructs were used, both containing cDNA encoding human γc. The Harvey-based vector transduced into cytokine-primed marrow yielded persistent detectable provirus in bone marrow and blood and expression of human γc on peripheral lymphocytes. In three dogs, human γc expression disappeared after 19 to 34 weeks but reappeared and was sustained, in one dog beyond 16 months posttransplantation, upon immunosuppression with cyclosporin A and prednisone, with up to 25% of lymphocytes expressing human γc. The long-term expression of human γc in a high proportion of normal canine lymphocytes predicts that retrovirus-mediated gene correction of hematopoietic cells may prove to be of clinical benefit in humans affected with this XSCID. This is a US government work. There are no restrictions on its use.

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42

Fayen, John D. "Multiple cytokines sharing the common receptor gamma chain can induce CD154/CD40 ligand expression by human CD4+ T lymphocytes via a cyclosporin A-resistant pathway." Immunology 104, no. 3 (November 2001): 299–306. http://dx.doi.org/10.1046/j.1365-2567.2001.01296.x.

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43

Soudais, Claire, Tsujino Shiho, Lama I. Sharara, Delphine Guy-Grand, Tadatsugu Taniguchi, Alain Fischer, and James P. Di Santo. "Stable and functional lymphoid reconstitution of common cytokine receptor γ chain deficient mice by retroviral-mediated gene transfer." Blood 95, no. 10 (May 15, 2000): 3071–77. http://dx.doi.org/10.1182/blood.v95.10.3071.

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Abstract Mutations in the gene encoding the common cytokine receptor gamma chain (γc) are responsible for human X-linked severe combined immunodeficiency disease (SCIDX1). We have used a γc-deficient mouse model to test the feasibility and potential toxicity of γc gene transfer as a therapy for SCIDX1. A retrovirus harboring the murine γc chain was introduced into γc-deficient bone marrow cells, which were then transplanted into alymphoid RAG2/γcdouble-deficient recipient mice. Circulating lymphocytes appeared 4 weeks postgraft and achieved steady-state levels by 8 weeks. The mature lymphocytes present in the grafted mice had integrated the γc transgene, expressed γc transcripts, and were able to proliferate in response to γc-dependent cytokines. The γc-transduced animals demonstrated (1) normal levels of immunoglobulin subclasses, including immunoglobulin G1 (IgG1) and IgG2a (which are severely decreased in γc- mice); (2) the ability to mount an antigen-specific, T-dependent antibody response showing effective in vivo T-B cell cooperation, and (3) the presence of gut-associated cryptopatches and intraepithelial lymphocytes. Importantly, peripheral B and T cells were still present 47 weeks after a primary graft, and animals receiving a secondary graft of γc-transduced bone marrow cells demonstrated peripheral lymphoid reconstitution. That γc gene transfer to hematopoietic precursor cells can correct the immune system abnormalities in γc- mice supports the feasibility of in vivo retroviral gene transfer as a treatment for human SCIDX1.

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44

Soudais, Claire, Tsujino Shiho, Lama I. Sharara, Delphine Guy-Grand, Tadatsugu Taniguchi, Alain Fischer, and James P. Di Santo. "Stable and functional lymphoid reconstitution of common cytokine receptor γ chain deficient mice by retroviral-mediated gene transfer." Blood 95, no. 10 (May 15, 2000): 3071–77. http://dx.doi.org/10.1182/blood.v95.10.3071.010k06_3071_3077.

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Mutations in the gene encoding the common cytokine receptor gamma chain (γc) are responsible for human X-linked severe combined immunodeficiency disease (SCIDX1). We have used a γc-deficient mouse model to test the feasibility and potential toxicity of γc gene transfer as a therapy for SCIDX1. A retrovirus harboring the murine γc chain was introduced into γc-deficient bone marrow cells, which were then transplanted into alymphoid RAG2/γcdouble-deficient recipient mice. Circulating lymphocytes appeared 4 weeks postgraft and achieved steady-state levels by 8 weeks. The mature lymphocytes present in the grafted mice had integrated the γc transgene, expressed γc transcripts, and were able to proliferate in response to γc-dependent cytokines. The γc-transduced animals demonstrated (1) normal levels of immunoglobulin subclasses, including immunoglobulin G1 (IgG1) and IgG2a (which are severely decreased in γc- mice); (2) the ability to mount an antigen-specific, T-dependent antibody response showing effective in vivo T-B cell cooperation, and (3) the presence of gut-associated cryptopatches and intraepithelial lymphocytes. Importantly, peripheral B and T cells were still present 47 weeks after a primary graft, and animals receiving a secondary graft of γc-transduced bone marrow cells demonstrated peripheral lymphoid reconstitution. That γc gene transfer to hematopoietic precursor cells can correct the immune system abnormalities in γc- mice supports the feasibility of in vivo retroviral gene transfer as a treatment for human SCIDX1.

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45

Villa, A., M. Sironi, P. Macchi, C. Matteucci, LD Notarangelo, P. Vezzoni, and A. Mantovani. "Monocyte function in a severe combined immunodeficient patient with a donor splice site mutation in the Jak3 gene." Blood 88, no. 3 (August 1, 1996): 817–23. http://dx.doi.org/10.1182/blood.v88.3.817.817.

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Abstract Janus kinase-3 (Jak3) is a nonreceptor tyrosine kinase functionally coupled to cytokine receptors which share a “common” gamma chain (gamma c). Mutations in gamma c and Jak3 genes have been identified in X- linked and autosomal severe combined immuno deficiency (SCID), respectively. Jak3 is expressed and activated in myelomonocytic cells. The present study was designed to define the structural alteration responsible for lack of Jak3 in a patient with autosomal SCID and to characterize monocyte function in the absence of this signal transduction element, as well as to establish the whole exon-intron structure. Polymerase chain reaction analysis, performed with primers designed on exon sequences, identified 20 exons spanning approximately 15 kb. These primers, or others designed on the flanking sequences provided in the present report, can be used to amplify the whole gene, allowing the definition of the molecular defects in all cases, including prenatal diagnosis, in which transcript analysis is not possible. On this basis, the deletion transcript found at the homozygous state in patient CM, with both his consanguineous parents being heterozygous for the deletion, was associated with mutation (T to C) of a splice donor site of intron 16 that was also detected in his mother's DNA. Monocytes from Jak3-SCID showed normal cytokine production in response to interleukin-4 (IL-4) (release of IL-1 receptor antagonist) and IL-2 (release of tumor necrosis factor-alpha and IL-8). Lipopolysaccharide-induced cytokine production was also normal and was blocked by IL-4 in Jak3- SCID monocytes. Interferon- gamma induced augmented expression of major histocompatibility class II in Jak3-SCID monocytes. These data indicate that Jak3, expressed and activated in myelomonocytic cells, is dispensable for monocyte differentiation and responsiveness to cytokines that interact with gamma c receptors as well as to other regulatory signals.

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46

Villa, A., M. Sironi, P. Macchi, C. Matteucci, LD Notarangelo, P. Vezzoni, and A. Mantovani. "Monocyte function in a severe combined immunodeficient patient with a donor splice site mutation in the Jak3 gene." Blood 88, no. 3 (August 1, 1996): 817–23. http://dx.doi.org/10.1182/blood.v88.3.817.bloodjournal883817.

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Janus kinase-3 (Jak3) is a nonreceptor tyrosine kinase functionally coupled to cytokine receptors which share a “common” gamma chain (gamma c). Mutations in gamma c and Jak3 genes have been identified in X- linked and autosomal severe combined immuno deficiency (SCID), respectively. Jak3 is expressed and activated in myelomonocytic cells. The present study was designed to define the structural alteration responsible for lack of Jak3 in a patient with autosomal SCID and to characterize monocyte function in the absence of this signal transduction element, as well as to establish the whole exon-intron structure. Polymerase chain reaction analysis, performed with primers designed on exon sequences, identified 20 exons spanning approximately 15 kb. These primers, or others designed on the flanking sequences provided in the present report, can be used to amplify the whole gene, allowing the definition of the molecular defects in all cases, including prenatal diagnosis, in which transcript analysis is not possible. On this basis, the deletion transcript found at the homozygous state in patient CM, with both his consanguineous parents being heterozygous for the deletion, was associated with mutation (T to C) of a splice donor site of intron 16 that was also detected in his mother's DNA. Monocytes from Jak3-SCID showed normal cytokine production in response to interleukin-4 (IL-4) (release of IL-1 receptor antagonist) and IL-2 (release of tumor necrosis factor-alpha and IL-8). Lipopolysaccharide-induced cytokine production was also normal and was blocked by IL-4 in Jak3- SCID monocytes. Interferon- gamma induced augmented expression of major histocompatibility class II in Jak3-SCID monocytes. These data indicate that Jak3, expressed and activated in myelomonocytic cells, is dispensable for monocyte differentiation and responsiveness to cytokines that interact with gamma c receptors as well as to other regulatory signals.

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47

Schumann, RR, T. Nakarai, HJ Gruss, MA Brach, U. von Arnim, C. Kirschning, L. Karawajew, et al. "Transcript synthesis and surface expression of the interleukin-2 receptor (alpha-, beta-, and gamma-chain) by normal and malignant myeloid cells." Blood 87, no. 6 (March 15, 1996): 2419–27. http://dx.doi.org/10.1182/blood.v87.6.2419.bloodjournal8762419.

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Expression of the interleukin-2 receptor alpha-(IL-2Ralpha-), IL-2Rbeta- , and the recently identified IL-2Rgamma-chain was examined on a wide range of cells of myeloid origin including neutrophils, monocytes, normal bone marrow-derived myeloid progenitors enriched for CD34+ cells, bone marrow blasts obtained from acute myelogenous leukemia (AML) patients, and permanent myeloid leukemia cell lines by reverse transcriptase-polymerase chain reaction and surface membrane analysis using receptor chain-specific monoclonal antibodies and flow cytometry. Expression of the p75 IL-2Rbeta- and the p64 IL-2Rgamma-chain was a common finding in most of the myeloid cell samples investigated, whereas IL-2Ralpha-chain was less frequently expressed. Although the high-affinity IL-2R form (ie, the alpha+, beta+, gamma+ IL-2R form) was detectable in a small minority of primary AML samples as well as the KG- 1 cell line and IL-2 binding to these cells was sufficient to initiate signal transduction as evidenced by an increase in overall protein tyrosine phosphorylation and more specifically in tyrosine phosphorylation of the Janus kinase (JAK) 3, in none of these cell types did exposure to IL-2 affect cell growth kinetics. These results suggest that, in myeloid cells, the IL-2R may not stimulate mitogenic responses or that its components may be expressed in a combinational association with receptors for other cytokines and that IL-2Rgamma may play a regulatory role in normal and malignant myelopoiesis possibly independent from IL-2. Because recent studies by others have indicated that the IL-2Rgamma- chain may be shared by the IL-4R, the IL-7R, and most likely the IL-9R, expression of mRNA of these receptor types was also investigated in these cell samples. Surprisingly, in a substantial part of the myeloid lineage cells examined, an IL-2Rgamma+, IL-4R-, IL7R- configuration was noted that was, however, frequently associated with expression of IL-9R. Sharing of IL-9R/IL-2R components was furthermore suggested by inhibition of 125I-IL-2 binding to primary AML cells with excess of unlabeled IL-9.

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Trinité, Benjamin, Chi N. Chan, Caroline S. Lee, and David N. Levy. "Erratum for Trinité et al., HIV-1 Vpr- and Reverse Transcription-Induced Apoptosis in Resting Peripheral Blood CD4 T Cells and Protection by Common Gamma-Chain Cytokines." Journal of Virology 90, no. 16 (July 27, 2016): 7593. http://dx.doi.org/10.1128/jvi.01100-16.

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Sitnicka, Ewa, Cord Brakebusch, Inga-Lill Martensson, Marcus Svensson, William W. Agace, Mikael Sigvardsson, Natalija Buza-Vidas, et al. "Complementary Signaling through flt3 and Interleukin-7 Receptor α Is Indispensable for Fetal and Adult B Cell Genesis." Journal of Experimental Medicine 198, no. 10 (November 10, 2003): 1495–506. http://dx.doi.org/10.1084/jem.20031152.

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Extensive studies of mice deficient in one or several cytokine receptors have failed to support an indispensable role of cytokines in development of multiple blood cell lineages. Whereas B1 B cells and Igs are sustained at normal levels throughout life of mice deficient in IL-7, IL-7Rα, common cytokine receptor gamma chain, or flt3 ligand (FL), we report here that adult mice double deficient in IL-7Rα and FL completely lack visible LNs, conventional IgM+ B cells, IgA+ plasma cells, and B1 cells, and consequently produce no Igs. All stages of committed B cell progenitors are undetectable in FL−/− × IL-7Rα−/− BM that also lacks expression of the B cell commitment factor Pax5 and its direct target genes. Furthermore, in contrast to IL-7Rα−/− mice, FL−/− × IL-7Rα−/− mice also lack mature B cells and detectable committed B cell progenitors during fetal development. Thus, signaling through the cytokine tyrosine kinase receptor flt3 and IL-7Rα are indispensable for fetal and adult B cell development.

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Metcalfe, Clive, Peter Cresswell, and A. Neil Barclay. "Interleukin-2 signalling is modulated by a labile disulfide bond in the CD132 chain of its receptor." Open Biology 2, no. 1 (January 2012): 110036. http://dx.doi.org/10.1098/rsob.110036.

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Certain disulfide bonds present in leucocyte membrane proteins are labile and can be reduced in inflammation. This can cause structural changes that result in downstream functional effects, for example, in integrin activation. Recent studies have shown that a wide range of membrane proteins have labile disulfide bonds including CD132, the common gamma chain of the receptors for several cytokines including interleukin-2 and interleukin-4 (IL-2 and IL-4). The Cys 183 –Cys 232 disulfide bond in mouse CD132 is susceptible to reduction by enzymes such as thioredoxin (TRX), gamma interferon-inducible lysosomal thiolreductase and protein disulfide isomerase, which are commonly secreted during immune activation. The Cys 183 –Cys 232 disulfide bond is also reduced in an in vivo lipopolysaccharide (LPS)-induced acute model of inflammation. Conditions that lead to the reduction of the Cys 183 –Cys 232 disulfide bond in CD132 inhibit proliferation of an IL-2-dependent T cell clone and concomitant inhibition of the STAT-5 signalling pathway. The same reducing conditions had no effect on the proliferation of an IL-2-independent T cell clone, nor did they reduce disulfide bonds in IL-2 itself. We postulate that reduction of the Cys 183 –Cys 232 disulfide in CD132 inhibits IL-2 binding to the receptor complex. Published data show that the Cys 183 –Cys 232 disulfide bond is exposed at the surface of CD132 and in close contact with IL-2 and IL-4 in their respective receptor complexes. In addition, mutants in these Cys residues in human CD132 lead to immunodeficiency and loss of IL-2 binding. These results have wider implications for the regulation of cytokine receptors in general, as their activity can be modulated by a ‘redox regulator’ mechanism caused by the changes in the redox environment that occur during inflammation and activation of the immune system.

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Journal articles on the topic 'Sequential common gamma chain cytokines'

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