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Journal articles on the topic 'IL-15Rα'

Author: Grafiati
Published: 4 June 2021
Last updated: 1 February 2022

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1

Burkett, Patrick R., Rima Koka, Marcia Chien, Sophia Chai, David L. Boone, and Averil Ma. "Coordinate Expression and Trans Presentation of Interleukin (IL)-15Rα and IL-15 Supports Natural Killer Cell and Memory CD8+ T Cell Homeostasis." Journal of Experimental Medicine 200, no. 7 (September 27, 2004): 825–34. http://dx.doi.org/10.1084/jem.20041389.

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The high affinity interleukin (IL)-15 receptor, IL-15Rα, is essential for supporting lymphoid homeostasis. To assess whether IL-15Rα's role in vivo is to trans present IL-15, we generated mixed bone marrow chimera from IL-15Rα– and IL-2/15Rβ–deficient mice. We find that IL-15Rα–competent, IL-2/15Rβ–deficient cells are able to support IL-15Rα–deficient natural killer (NK) and memory CD8+ T cells, thus ruling out secondary signals on these cells and demonstrating that IL-15Rα–mediated presentation of IL-15 in trans is the primary mechanism by which IL-15Rα functions in vivo. Surprisingly, using IL-15– and IL-15Rα–deficient mixed chimera, we also find that IL-15 and IL-15Rα must be expressed by the same cells to present IL-15 in trans, indicating that IL-15Rα is required on a cellular level for the elaboration of IL-15. These studies indicate that IL-15Rα defines homeostatic niches for NK and memory CD8+ T cells by controlling both the production and the presentation of IL-15 in trans to NK and CD8+ memory T cells.
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2

Loro, Emanuele, Erin L. Seifert, Cynthia Moffat, Freddy Romero, Manoj K. Mishra, Zheng Sun, Predrag Krajacic, et al. "IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 309, no. 8 (October 15, 2015): R835—R844. http://dx.doi.org/10.1152/ajpregu.00505.2014.

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IL-15Rα is the widely expressed primary binding partner for IL-15. Because of the wide distribution in nonlymphoid tissues like skeletal muscle, adipose, or liver, IL-15/IL-15Rα take part in physiological and metabolic processes not directly related to immunity. In fast muscle, lack of IL-15Rα promotes an oxidative switch, with increased mitochondrial biogenesis and fatigue resistance. These effects are predicted to reproduce some of the benefits of exercise and, therefore, improve energy homeostasis. However, the direct effects of IL-15Rα on metabolism and obesity are currently unknown. We report that mice lacking IL-15Rα (IL-15Rα−/−) are resistant to diet-induced obesity (DIO). High-fat diet-fed IL-15Rα−/− mice have less body and liver fat accumulation than controls. The leaner phenotype is associated with increased energy expenditure and enhanced fatty acid oxidation by muscle mitochondria. Despite being protected against DIO, IL-15Rα−/− are hyperglycemic and insulin-resistant. These findings identify novel roles for IL-15Rα in metabolism and obesity.
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3

Mortier, Erwan, Tammy Woo, Rommel Advincula, Sara Gozalo, and Averil Ma. "IL-15Rα chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation." Journal of Experimental Medicine 205, no. 5 (May 5, 2008): 1213–25. http://dx.doi.org/10.1084/jem.20071913.

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Natural killer (NK) cells are innate immune effectors that mediate rapid responses to viral antigens. Interleukin (IL)-15 and its high affinity IL-15 receptor, IL-15Rα, support NK cell homeostasis in resting animals via a novel trans presentation mechanism. To better understand how IL-15 and IL-15Rα support NK cell activation during immune responses, we have used sensitive assays for detecting native IL-15 and IL-15Rα proteins and developed an assay for detecting complexes of these proteins. We find that IL-15 and IL-15Rα are preassembled in complexes within the endoplasmic reticulum/Golgi of stimulated dendritic cells (DCs) before being released from cells. IL-15Rα is required for IL-15 production by DCs, and IL-15 that emerges onto the cell surface of matured DCs does not bind to neighboring cells expressing IL-15Rα. We also find that soluble IL-15–IL-15Rα complexes are induced during inflammation, but membrane-bound IL-15–IL-15Rα complexes, rather than soluble complexes, support NK cell activation in vitro and in vivo. Finally, we provide in vivo evidence that expression of IL-15Rα specifically on DCs is critical for trans presenting IL-15 and activating NK cells. These studies define an unprecedented cytokine–receptor biosynthetic pathway in which IL-15Rα serves as a chaperone for IL-15, after which membrane-bound IL-15Rα–IL-15 complexes activate NK cells via direct cell–cell contact.
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4

Anderson, Barbara G., and LeBris S. Quinn. "Free IL-15 Is More Abundant Than IL-15 Complexed With Soluble IL-15 Receptor-α in Murine Serum: Implications for the Mechanism of IL-15 Secretion." Endocrinology 157, no. 3 (January 26, 2016): 1315–20. http://dx.doi.org/10.1210/en.2015-1746.

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Abstract IL-15 is a cytokine that is part of the innate immune system, as well as a proposed myokine released from skeletal muscle during physical exercise that mediates many of the positive physiological effects of exercise. Many of the immune functions of IL-15 are mediated by juxtacrine signaling via externalized IL-15 bound to membrane-associated IL-15 receptor-α (IL-15Rα). Serum and plasma samples also contain measurable concentrations of IL-15, believed to arise from proteolytic cleavage of membrane-associated IL-15/IL-15Rα complexes to generate soluble IL-15/IL-15Rα species. Here, we validate commercial assays that can distinguish the free form of IL-15 and IL-15/IL-15Rα complexes. These assays showed that most (86%) IL-15 in mouse serum resides in the free state, with a minor proportion (14%) residing in complex with IL-15Rα. Given the much shorter half-life of free IL-15 compared with IL-15/IL-15Rα complexes, these findings cast doubt on the currently accepted model for IL-15 secretion from cleavage of membrane-bound IL-15/IL-15Rα and suggest that IL-15 is released as a free molecule by an unknown mechanism.
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5

Lodolce, James P., Patrick R. Burkett, David L. Boone, Marcia Chien, and Averil Ma. "T Cell–Independent Interleukin 15rα Signals Are Required for Bystander Proliferation." Journal of Experimental Medicine 194, no. 8 (October 15, 2001): 1187–94. http://dx.doi.org/10.1084/jem.194.8.1187.

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Cytokine driven or “bystander” proliferation of T cells occurs in vivo independently of major histocompatibility complex–T cell receptor interactions. This process may be important for supporting T cell homeostasis and facilitating T cell responses to microbial antigens, and may involve the cytokine interleukin (IL)-15. In this study, we find that IL-15Rα–deficient (IL-15Rα−/−) mice fail to undergo poly I:C or IL-15 driven bystander proliferation of CD8+ T cells. Surprisingly, IL-15Rα−/− CD8+ T cells proliferate in response to poly I:C when adoptively transferred into normal mice, and normal CD8+ T cells fail to proliferate in IL-15Rα−/− mice. Normal mice reconstituted with IL-15Rα−/− bone marrow cells also fail to exhibit bystander responses. Thus, CD8+ T cell independent IL-15Rα signals from radiation sensitive hematopoietic cells are likely required for bystander responses. Moreover, normal CD8+ T cells proliferate in IL-15Rα−/− mice after treatment with IL-15. Therefore, IL-15Rα signals may mediate a positive feedback loop involving the further physiological production of IL-15. These findings provide new insights into how IL-15Rα supports memory phenotype CD8+ T cell proliferation, and suggest novel mechanisms by which memory CD8+ T cells are maintained in vivo.
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6

Koka, Rima, Patrick R. Burkett, Marcia Chien, Sophia Chai, Faye Chan, James P. Lodolce, David L. Boone, and Averil Ma. "Interleukin (IL)-15Rα–deficient Natural Killer Cells Survive in Normal but Not IL-15Rα–deficient Mice." Journal of Experimental Medicine 197, no. 8 (April 14, 2003): 977–84. http://dx.doi.org/10.1084/jem.20021836.

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Natural killer (NK) cells protect hosts against viral pathogens and transformed cells. IL-15 is thought to play a critical role in NK cell development, but its role in the regulation of peripheral NK cells is less well defined. We now find that adoptive transfer of normal NK cells into mice lacking the high affinity interleukin (IL)-15 receptor, IL-15Rα, surprisingly results in the abrupt loss of these cells. Moreover, IL-15Rα–deficient NK cells can differentiate successfully in radiation bone marrow chimera bearing normal cells. Finally, adoptively transferred IL-15Rα–deficient NK cells survive in normal but not IL-15Rα–deficient mice. These findings demonstrate that NK cell–independent IL-15Rα expression is critical for maintaining peripheral NK cells, while IL-15Rα expression on NK cells is not required for this function.
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7

Wu, Zheng, Hai-Hui Xue, Jérôme Bernard, Rong Zeng, Dmitry Issakov, Julie Bollenbacher-Reilley, Igor M. Belyakov, SangKon Oh, Jay A. Berzofsky, and Warren J. Leonard. "The IL-15 receptor α chain cytoplasmic domain is critical for normal IL-15Rα function but is not required for trans-presentation." Blood 112, no. 12 (December 1, 2008): 4411–19. http://dx.doi.org/10.1182/blood-2007-03-080697.

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AbstractIL-15 is critical for natural killer (NK)–cell development and function and for memory CD8+ T-cell homeostasis. The IL-15 receptor consists of IL-15Rα, IL-2Rβ, and the common cytokine receptor γ chain (γc). IL-15Rα is known to “trans-present” IL-15 to an IL-2Rβ/γc heterodimeric receptor on responding cells to initiate signaling. To investigate the importance of the IL-15Rα cytoplasmic domain, we generated a chimeric receptor consisting of the extracellular domain of IL-15Rα and intracellular domain of IL-2Rα (IL-15Rαext/IL-2Rαint) and examined its function in 32D cells, in knock-in (KI) mice, and in adoptive-transfer experiments. The chimeric protein exhibited decreased cell-surface expression, and KI mice exhibited diminished NK, NKT, and CD8+ T-cell development and defects in T-cell functional responses. However, 32D cells expressing the chimeric receptor had less IL-15–induced proliferation than wild-type (WT) transfectants with similar levels of IL-15Rα expression, indicating a signaling role for the IL-15Rα cytoplasmic domain beyond its effect on expression, and demonstrating that the IL-2Rα and IL-15Rα cytoplasmic domains are functionally distinct. Interestingly, adoptive-transfer experiments indicated that the chimeric IL-15Rαext/IL-2Rαint receptor still supports trans-presentation. These experiments collectively indicate that IL-15Rα can act in cis in addition to acting in trans to present IL-15 to responding cells.
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8

Colpitts, Sara L., Lynn Puddington, and Leo Lefrançois. "IL-15 receptor α signaling constrains the development of IL-17–producing γδ T cells." Proceedings of the National Academy of Sciences 112, no. 31 (July 20, 2015): 9692–97. http://dx.doi.org/10.1073/pnas.1420741112.

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The development and homeostasis of γδ T cells is highly dependent on distinct cytokine networks. Here we examine the role of IL-15 and its unique receptor, IL-15Rα, in the development of IL-17–producing γδ (γδ-17) T cells. Phenotypic analysis has shown that CD44high γδ-17 cells express IL-15Rα and the common gamma chain (CD132), yet lack the IL-2/15Rβ chain (CD122). Surprisingly, we found an enlarged population of γδ-17 cells in the peripheral and mesenteric lymph nodes of adult IL-15Rα KO mice, but not of IL-15 KO mice. The generation of mixed chimeras from neonatal thymocytes indicated that cell-intrinsic IL-15Rα expression was required to limit IL-17 production by γδ T cells. γδ-17 cells also were increased in the peripheral lymph nodes of transgenic knock-in mice, where the IL-15Rα intracellular signaling domain was replaced with the intracellular portion of the IL-2Rα chain (that lacks signaling capacity). Finally, an analysis of neonatal thymi revealed that the CD44lo/int precursors of γδ-17 cells, which also expressed IL-15Rα, were increased in newborn mice deficient in IL-15Rα signaling, but not in IL-15 itself. Thus, these findings demonstrate that signaling through IL-15Rα regulates the development of γδ-17 cells early in ontogeny, with long-term effects on their peripheral homeostasis in the adult.
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9

Schluns, Kimberly S., Kimberly D. Klonowski, and Leo Lefrançois. "Transregulation of memory CD8 T-cell proliferation by IL-15Rα+ bone marrow–derived cells." Blood 103, no. 3 (February 1, 2004): 988–94. http://dx.doi.org/10.1182/blood-2003-08-2814.

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AbstractInterleukin 15 (IL-15) and the IL-15 receptor α (IL-15Rα) chain are both required for the basal proliferation of memory CD8 T cells, but which cell types are required to express IL-15 or IL-15Rα to mediate this proliferation is not known. Using bone marrow (BM) chimeras, we showed that virus-specific CD8 memory T-cell proliferation was driven by IL-15 produced by either BM-derived or parenchymal cells. Experiments using mixed BM chimeras showed that IL-15Rα expression by memory CD8 T cells was not required for their division. In addition, wild-type memory CD8 T cells did not divide after transfer into IL-15Rα-/- mice. Further analyses demonstrated that IL-15Rα+ BM-derived cells were crucial in driving memory CD8 T-cell division in the spleen while both parenchymal and BM-derived cells promoted memory cell division in the lung. Proliferation in response to soluble IL-15 in vivo required expression of IL-15Rα by opposing cells and IL-15Rβ by CD8 memory cells, indicating that IL-15 interacted directly with the T cells. These results indicate that transpresentation of IL-15 by IL-15Rα on BM-derived cells mediates the basal proliferation of memory CD8 T cells. (Blood. 2004;103:988-994)
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10

Chen, Jing, Mike Petrus, Richard Bamford, Joanna H. Shih, John C. Morris, John E. Janik, and Thomas A. Waldmann. "Increased serum soluble IL-15Rα levels in T-cell large granular lymphocyte leukemia." Blood 119, no. 1 (January 5, 2012): 137–43. http://dx.doi.org/10.1182/blood-2011-04-346759.

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AbstractLarge granular lymphocyte (LGL) leukemia is a clonal lymphoproliferative disease of mature T and natural killer cells. The etiology of LGL leukemia is unknown. IL-15 is an inflammatory cytokine that stimulates T and natural killer cells and is critical for their survival and proliferation. IL-15 signals through a heterotrimeric receptor that is composed of a private receptor, IL-15Rα and IL-2/IL-15Rβ and γc shared with IL-2. Using a newly developed assay, we demonstrated increased levels of soluble IL-15Rα in the serum of patients with T-LGL leukemia. Furthermore, IL-15Rα mRNA levels were also up-regulated in the PBMCs of these patients. FACS analysis indicated that IL-15Rα was expressed both on monocytes as well as on some CD8+ leukemic cells of the patients. Interestingly, the mRNA levels of IFN-γ, a known inducer of IL-15Rα, were also up-regulated in patients' PBMCs. Moreover, PBMCs of some T-LGL patients proliferated at higher levels in response to exogenously added IL-15 compared with those of normal donors. In summary, our study demonstrated increased expression of IL-15Rα in T-LGL leukemia. It is conceivable that higher IL-15Rα expression may lower IL-15 response threshold in vivo and, therefore, may contribute to the pathogenesis of the disease.
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11

Sato, Noriko, Helen Sabzevari, Song Fu, Wei Ju, Michael N. Petrus, Richard N. Bamford, Thomas A. Waldmann, and Yutaka Tagaya. "Development of an IL-15–autocrine CD8 T-cell leukemia in IL-15–transgenic mice requires the cis expression of IL-15Rα." Blood 117, no. 15 (April 14, 2011): 4032–40. http://dx.doi.org/10.1182/blood-2010-09-307504.

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AbstractIL-15 has growth-promoting effects on select lymphoid subsets, including natural killer (NK) cells, NK T cells, intraepithelial lymphocytes (IELs), CD8 T cells, and γδ-T cells. Constitutive expression of murine IL-15 in IL-15–transgenic mice was reported to cause T-NK leukemia. We investigated whether IL-15 expression is sufficient for leukemic transformation using a human IL-15–transgenic (IL-15Tg) mouse model. We noted that 100% of the mice observed over a 2-year period (n > 150) developed fatal expansions of CD8 T cells with NK markers, and determined that these cells expressed IL-15 receptor alpha (IL-15Rα). The expression of IL-15Rα on CD8 T cells appears to be required for uncontrolled aggressive lymphoproliferation, because none of the IL-15Rα−/−–IL-15Tg mice that we followed for more than 2 years developed the fatal disease despite controlled expansion of CD8 T cells. In addition, in contrast to IL-15Tg mice, in which leukemia-like CD8 T cells expressed IL-15Rα persistently, acutely activated normal CD8 T cells only transiently expressed IL-15Rα. Inhibition of DNA methylation enabled sustained IL-15Rα expression induced by activation. We present a scenario for IL-15Tg mice in which CD8 T cells that acquire constitutive persistent IL-15Rα expression are at a selective advantage and become founder cells, outgrow other lymphocytes, and lead to the establishment of a leukemia-like condition.
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12

Shi, Yimin, Lillia Dincheva-Vogel, Charles E. Ayemoba, Jeffrey P. Fung, Cristina Bergamaschi, George N. Pavlakis, Farzin Farzaneh, and Karin M. L. Gaensler. "IL-15/IL-15Rα/CD80-expressing AML cell vaccines eradicate minimal residual disease in leukemic mice." Blood Advances 2, no. 22 (November 27, 2018): 3177–92. http://dx.doi.org/10.1182/bloodadvances.2018019026.

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AbstractEngineered autologous acute myeloid leukemia (AML) cells present multiple leukemia-associated and patient-specific antigens and as such hold promise as immunotherapeutic vaccines. However, prior vaccines have not reliably induced effective antileukemic immunity, in part because AML blasts have immune inhibitory effects and lack expression of the critical costimulatory molecule CD80. To enhance induction of leukemia-specific cytolytic activity, 32Dp210 murine AML cells were engineered to express either CD80 alone, or the immunostimulatory cytokine interleukin-15 (IL-15) with its receptor α (IL-15Rα), or heterodimeric IL-15/IL-15Rα together with CD80 and tested as irradiated cell vaccines. IL-15 is a γc-chain cytokine, with unique properties suited to stimulating antitumor immunity, including stimulation of both natural killer and CD8+ memory T cells. Coexpression of IL-15 and IL-15Rα markedly increases IL-15 stability and secretion. Non-tumor-bearing mice vaccinated with irradiated 32Dp210-IL-15/IL-15Rα/CD80 and challenged with 32Dp210 leukemia had greater survival than did mice treated with 32Dp210-CD80 or 32Dp210-IL-15/IL-15Rα vaccines, whereas no unvaccinated mice inoculated with leukemia survived. In mice with established leukemia, treatment with 32Dp210-IL-15/IL-15Rα/CD80 vaccination stimulated unprecedented antileukemic immunity enabling 80% survival, an effect that was abrogated by anti-CD8 antibody-mediated depletion in vivo. Because, clinically, AML vaccines are administered as postremission therapy, we established a novel model in which mice with high leukemic burdens were treated with cytotoxic therapy to induce remission (<5% marrow blasts). Postremission vaccination with 32Dp210-IL-15/IL-15Rα/CD80 achieved 50% overall survival in these mice, whereas all unvaccinated mice achieving remission subsequently relapsed. These studies demonstrate that combined expression of IL-15/IL-15Rα and CD80 by syngeneic AML vaccines stimulates effective and long-lasting antileukemic immunity.
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13

Bouchaud, Grégory, Samuel Gehrke, Carsten Krieg, Antonios Kolios, Jürg Hafner, Alexander A. Navarini, Lars E. French, and Onur Boyman. "Epidermal IL-15Rα acts as an endogenous antagonist of psoriasiform inflammation in mouse and man." Journal of Experimental Medicine 210, no. 10 (September 9, 2013): 2105–17. http://dx.doi.org/10.1084/jem.20130291.

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Stromal cells at epithelial surfaces contribute to innate immunity by sensing environmental danger signals and producing proinflammatory cytokines. However, the role of stromal cells in controlling local inflammation is unknown. We show that endogenous soluble IL-15 receptor α (IL-15Rα) derived from epidermal stroma, notably keratinocytes, protects against dendritic cell/IL-15-mediated, T cell-driven skin inflammation in vivo, and is relevant to human psoriasis. Selective lack of IL-15Rα on stromal epidermal cells exacerbated psoriasiform inflammation in animals. Epidermal IL-15Rα was shed by keratinocytes via proteolytic cleavage by matrix metalloproteinases upon stimulation with proinflammatory cytokines to counteract IL-15–induced proliferation of IL-17+ αβ and γδ T cells and production of TNF, IL-23, IL-17, and IL-22 during skin inflammation. Notably, administration of soluble IL-15Rα was able to repress secretion of IL-1β, IL-6, and TNF by keratinocytes, dampen expansion of IL-17+ αβ and γδ T cells in vivo, and prevent psoriasis in two mouse models, including human xenograft AGR mice. Serum levels of soluble IL-15Rα negatively correlated with disease severity, and levels rose upon successful treatment of psoriasis in patients. Thus, stressed epidermal stromal cells use soluble IL-15Rα to dampen chronic inflammatory skin disease.
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14

Do-Thi, Van Anh, Hayyoung Lee, Hye Jin Jeong, Jie-Oh Lee, and Young Sang Kim. "Protective and Therapeutic Effects of an IL-15:IL-15Rα-Secreting Cell-Based Cancer Vaccine Using a Baculovirus System." Cancers 13, no. 16 (August 11, 2021): 4039. http://dx.doi.org/10.3390/cancers13164039.

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This study reports the use of the BacMam system to deliver and express self-assembling IL-15 and IL-15Rα genes to murine B16F10 melanoma and CT26 colon cancer cells. BacMam-based IL-15 and IL-15Rα were well-expressed and assembled to form the biologically functional IL-15:IL-15Rα complex. Immunization with this IL-15:IL-15Rα cancer vaccine delayed tumor growth in mice by inducing effector memory CD4+ and CD8+ cells and effector NK cells which are tumor-infiltrating. It caused strong antitumor immune responses of CD8+ effector cells in a tumor-antigen specific manner both in vitro and in vivo and significantly attenuated Treg cells which a control virus-infected cancer vaccine could induce. Post-treatment with this cancer vaccine after a live cancer cell injection also prominently delayed the growth of the tumor. Collectively, we demonstrate a vaccine platform consisting of BacMam virus-infected B16F10 or CT26 cancer cells that secrete IL-15:IL-15Rα. This study is the first demonstration of a functionally competent soluble IL-15:IL-15Rα complex-related cancer vaccine using a baculovirus system and advocates that the BacMam system can be used as a secure and rapid method of producing a protective and therapeutic cancer vaccine.
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15

Duitman, Erwin H., Zane Orinska, Elena Bulanova, Ralf Paus, and Silvia Bulfone-Paus. "How a Cytokine Is Chaperoned through the Secretory Pathway by Complexing with Its Own Receptor: Lessons from Interleukin-15 (IL-15)/IL-15 Receptor α." Molecular and Cellular Biology 28, no. 15 (May 27, 2008): 4851–61. http://dx.doi.org/10.1128/mcb.02178-07.

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ABSTRACTWhile it is well appreciated that receptors for secreted cytokines transmit ligand-induced signals, little is known about additional roles for cytokine receptor components in the control of ligand transport and secretion. Here, we show that interleukin-15 (IL-15) translocation into the endoplasmic reticulum occurs independently of the presence of IL-15 receptor α (IL-15Rα). Subsequently, however, IL-15 is transported through the Golgi apparatus only in association with IL-15Rα and then is secreted. This intracellular IL-15/IL-15Rα complex already is formed in the endoplasmic reticulum and, thus, enables the further trafficking of complexed IL-15 through the secretory pathway. Just transfecting IL-15Rα in cells, which transcribe but normally do not secrete IL-15, suffices to induce IL-15 secretion. Thus, we provide the first evidence of how a cytokine is chaperoned through the secretory pathway by complexing with its own high-affinity receptor and show that IL-15/IL-15Rα offers an excellent model system for the further exploration of this novel mechanism for the control of cytokine secretion.
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16

Machado Diaz, Ana Cecilia, Araceli Chico Capote, Celia Aurora Arrieta Aguero, Yunier Rodríguez Alvarez, Diana García del Barco Herrera, Miguel Estévez del Toro, Gerardo E. Guillen Nieto, and Alicia Santos Savio. "Proinflammatory Soluble Interleukin-15 Receptor Alpha Is Increased in Rheumatoid Arthritis." Arthritis 2012 (July 25, 2012): 1–7. http://dx.doi.org/10.1155/2012/943156.

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Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease in which many cytokines have been implicated. In particular, IL-15 is a cytokine involved in the inflammatory processes and bone loss. The aim of this study was to investigate the existence in synovial fluid of soluble IL-15Rα, a private receptor subunit for IL-15 which may act as an enhancer of IL-15-induced proinflammatory cytokines. Soluble IL-15Rα was quantified by a newly developed enzyme-linked immunosorbent assay (ELISA) in samples of synovial fluid from patients with RA and osteoarthritis (OA). The levels of IL-15Rα were significantly increased in RA patients compared to OA patients. Also, we studied the presence of membrane-bound IL-15 in cells from synovial fluids, another element necessary to induce pro-inflammatory cytokines through reverse signaling. Interestingly, we found high levels of IL-6 related to high levels of IL-15Rα in RA but not in OA. Thus, our results evidenced presence of IL-15Rα in synovial fluids and suggested that its pro-inflammatory effect could be related to induction of IL-6.
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17

Bergamaschi, Cristina, Jenifer Bear, Margherita Rosati, Rachel Kelly Beach, Candido Alicea, Raymond Sowder, Elena Chertova, Steven A. Rosenberg, Barbara K. Felber, and George N. Pavlakis. "Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum." Blood 120, no. 1 (July 5, 2012): e1-e8. http://dx.doi.org/10.1182/blood-2011-10-384362.

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Abstract IL-15 is an important cytokine for the function of the immune system, but the form(s) of IL-15 produced in the human body are not fully characterized. Coexpression of the single-chain IL-15 and the IL-15 receptor alpha (IL-15Rα) in the same cell allows for efficient production, surface display, and eventual cleavage and secretion of the bioactive IL-15/IL-15Rα heterodimer in vivo, whereas the single-chain IL-15 is poorly secreted and unstable. This observation led to the hypothesis that IL-15 is produced and secreted only as a heterodimer with IL-15Rα. We purified human IL-15/IL-15Rα complexes from overproducing human cell lines and developed an ELISA specifically measuring the heterodimeric form of IL-15. Analysis of sera from melanoma patients after lymphodepletion revealed the presence of circulating IL-15/IL-15Rα complexes in amounts similar to the total IL-15 quantified by a commercial IL-15 ELISA that detects both the single-chain and the heterodimeric forms of the cytokine. Therefore, in lymphodepleted cancer patients, the serum IL-15 is exclusively present in its heterodimeric form. Analysis of the form of IL-15 present in either normal or lymphodepleted mice agrees with the human data. These results have important implications for development of assays and materials for clinical applications of IL-15.
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18

Pereno, Raffaele, Julien Giron-Michel, Alessia Gaggero, Eric Cazes, Raffaella Meazza, Monia Monetti, Eugenia Monaco, et al. "IL-15/IL-15Rα intracellular trafficking in human melanoma cells and signal transduction through the IL-15Rα." Oncogene 19, no. 45 (October 2000): 5153–62. http://dx.doi.org/10.1038/sj.onc.1203873.

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19

Anton, Olga M., Mary E. Peterson, Michael J. Hollander, David W. Dorward, Gunjan Arora, Javier Traba, Sumati Rajagopalan, et al. "Trans-endocytosis of intact IL-15Rα–IL-15 complex from presenting cells into NK cells favors signaling for proliferation." Proceedings of the National Academy of Sciences 117, no. 1 (December 23, 2019): 522–31. http://dx.doi.org/10.1073/pnas.1911678117.

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Interleukin 15 (IL-15) is an essential cytokine for the survival and proliferation of natural killer (NK) cells. IL-15 activates signaling by the β and common γ (γc) chain heterodimer of the IL-2 receptor throughtrans-presentation by cells expressing IL-15 bound to the α chain of the IL-15 receptor (IL-15Rα). We show here that membrane-associated IL-15Rα–IL-15 complexes are transferred from presenting cells to NK cells throughtrans-endocytosis and contribute to the phosphorylation of ribosomal protein S6 and NK cell proliferation. NK cell interaction with soluble or surface-bound IL-15Rα–IL-15 complex resulted in Stat5 phosphorylation and NK cell survival at a concentration or density of the complex much lower than required to stimulate S6 phosphorylation. Despite this efficient response, Stat5 phosphorylation was reduced after inhibition of metalloprotease-induced IL-15Rα–IL-15 shedding fromtrans-presenting cells, whereas S6 phosphorylation was unaffected. Conversely, inhibition oftrans-endocytosis by silencing of the small GTPase TC21 or expression of a dominant-negative TC21 reduced S6 phosphorylation but not Stat5 phosphorylation. Thus,trans-endocytosis of membrane-associated IL-15Rα–IL-15 provides a mode of regulating NK cells that is not afforded to IL-2 and is distinct from activation by soluble IL-15. These results may explain the strict IL-15 dependence of NK cells and illustrate how the cellular compartment in which receptor–ligand interaction occurs can influence functional outcome.
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Giron-Michel, Julien, Massimo Giuliani, Manuela Fogli, Danièle Brouty-Boyé, Silvano Ferrini, Florence Baychelier, Pierre Eid, et al. "Membrane-bound and soluble IL-15/IL-15Rα complexes display differential signaling and functions on human hematopoietic progenitors." Blood 106, no. 7 (October 1, 2005): 2302–10. http://dx.doi.org/10.1182/blood-2005-01-0064.

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AbstractMembrane-bound and soluble interleukin-15 (IL-15)/IL-15 receptor α (Rα) complexes trigger differential transcription factor activation and functions on human hematopoietic progenitors. Indeed, human spleen myofibroblasts (SMFs) are characterized by a novel mechanism of IL-15 trans-presentation (SMFmb [membrane-bound]-IL-15), based on the association of an endogenous IL-15/IL-15Rα complex with the IL-15Rβγc chains. SMFmb-IL-15 (1) induces lineage-specific signaling pathways that differ from those controlled by soluble IL-15 in unprimed and committed normal progenitors; (2) triggers survival and proliferation of leukemic progenitors expressing low-affinity IL-15R (M07Sb cells); (3) causes only an antiapoptotic effect on leukemic cells expressing high-affinity receptors (TF1β cells). This behavior is likely due to the IL-15Rα chain present on these cells that interact with the SMFmb-IL-15, inhibiting signal transducer and transcriptional activator 5 (STAT5) activation. On the other hand, the soluble IL-15/IL-15Rα complex (hyper IL-15) displays a dominant pattern of action, activating only those cells expressing low-affinity IL-15R (IL-15Rβγc). Thus, hyper IL-15 induces antiapoptotic effects on M075b cells and the up-regulation of STAT6 activation on adult peripheral blood (PB) pre-natural killer (NK) committed progenitors. The latter effect using 100-fold concentrations of recombinant (r)-IL-15. In conclusion, SMFmb-IL-15 and soluble IL-15Rα/IL-15 complexes seem to play a pivotal role in the control of the survival, proliferation and differentiation of both normal and leukemic circulating progenitors, highlighting new functions of IL-15 and of IL-15Rα.
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Pan, Yanli, Zhimin Wang, Guangping Zhang, Junhua Guo, Xuequan Zhu, Jia Zhou, Zhenrong Zhang, et al. "Schizophrenia Patient Shows a Rare Interleukin 15 Receptor alpha Variant Disrupting Signal Transduction." Current Molecular Medicine 19, no. 8 (September 5, 2019): 560–69. http://dx.doi.org/10.2174/1566524019666190617172054.

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Background: Schizophrenia is a complex and debilitating mental disorder with strong heritability. Its pathogenesis involves immune dysregulation. Interleukin 15 and interleukin 15 receptor alpha(IL-15Rα) are classical immune molecules. They also help maintain normal brain function, leading to our hypothesis that IL-15Rα gene(IL- 15RA) variants contribute to the pathogenesis of schizophrenia. Objective: We determine whether the genetic variants of IL-15RA are associated with the development and progression of schizophrenia and whether IL-15RA single nucleotide polymorphism(SNP) plays a key role in downstream signaling transduction. Methods and results: We sequenced IL-15RA exon from 132 Chinese schizophrenic patients and identified a rare variant(rs528238821) in a patient diagnosed with catatonic schizophrenia and ankylosing spondylitis(AS). We overexpressed this missense variant in cells driven by pBI-CMV vector. The cells showed attenuated STAT3 phosphorylation in response to interleukin15. Conclusion: IL-15RA mutation is rare in schizophrenic patients but interfered with IL- 15Rα intracellular signal transduction. Given the similarity of symptoms of catatonic schizophrenia and the known phenotype of IL-15Rα knockout mice, gene variation might offer diagnostic value for sub-types of schizophrenia.
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Sousa, Laurent, Quéméner, Mortier, and Questel. "Mechanistic and Structural Insights on the IL-15 System through Molecular Dynamics Simulations." Molecules 24, no. 18 (September 6, 2019): 3261. http://dx.doi.org/10.3390/molecules24183261.

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Interleukin 15 (IL-15), a four-helix bundle cytokine, is involved in a plethora of different cellular functions and, particularly, plays a key role in the development and activation of immune responses. IL-15 forms receptor complexes by binding with IL-2Rβ- and common γ(γc)-signaling subunits, which are shared with other members of the cytokines family (IL-2 for IL-2Rβ- and all other γc- cytokines for γc). The specificity of IL-15 is brought by the non-signaling α-subunit, IL-15Rα. Here we present the results of molecular dynamics simulations carried out on four relevant forms of IL-15: its monomer, IL-15 interacting individually with IL-15Rα (IL-15/IL-15Rα), with IL-2Rβ/γc subunits (IL-15/IL-2Rβ/γc) or with its three receptors simultaneously (IL-15/IL-15Rα/IL-2Rβ/γc). Through the analyses of the various trajectories, new insights on the structural features of the interfaces are highlighted, according to the considered form. The comparison of the results with the experimental data, available from X-ray crystallography, allows, in particular, the rationalization of the importance of IL-15 key residues (e.g. Asp8, Lys10, Glu64). Furthermore, the pivotal role of water molecules in the stabilization of the various protein-protein interfaces and their H-bonds networks are underlined for each of the considered complexes.
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Miyazaki, Takahiro, Mekhala Maiti, Marlene Hennessy, Thomas Chang, Peiwen Kuo, Murali Addepalli, Palakshi Obalapur, et al. "NKTR-255, a novel polymer-conjugated rhIL-15 with potent antitumor efficacy." Journal for ImmunoTherapy of Cancer 9, no. 5 (May 2021): e002024. http://dx.doi.org/10.1136/jitc-2020-002024.

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BackgroundNKTR-255 is a novel polyethylene glycol-conjugate of recombinant human interleukin-15 (rhIL-15), which was designed to retain all known receptor binding interactions of the IL-15 molecule. We explored the biologic and pharmacologic differences between endogenous IL-15 receptor α (IL-15Rα)-dependent (NKTR-255 and rhIL-15) and IL-15Rα-independent (precomplexed rhIL-15/IL-15Rα) cytokines.MethodsIn vitro pharmacological properties of rhIL-15, NKTR-255 and precomplex cytokines (rhIL-15/IL-15Rα and rhIL-15 N72D/IL-15Rα Fc) were investigated in receptor binding, signaling and cell function. In vivo pharmacokinetic (PK) and pharmacodynamic profile of the cytokines were evaluated in normal mice. Finally, immunomodulatory effect and antitumor activity were assessed in a Daudi lymphoma model.ResultsNKTR-255 and rhIL-15 exhibited similar in vitro properties in receptor affinity, signaling and leukocyte degranulation, which collectively differed from precomplexed cytokines. Notably, NKTR-255 and rhIL-15 stimulated greater granzyme B secretion in human peripheral blood mononuclear cells versus precomplexed cytokines. In vivo, NKTR-255 exhibited a PK profile with reduced clearance and a longer half-life relative to rhIL-15 and demonstrated prolonged IL-15R engagement in lymphocytes compared with only transient engagement observed for rhIL-15 and precomplexed rhIL-15 N72D/IL-15Rα Fc. As a consequent, NKTR-255 provided a durable and sustained proliferation and activation of natural killer (NK) and CD8+ T cells. Importantly, NKTR-255 is more effective than the precomplexed cytokine at inducing functionally competent, cytotoxic NK cells in the tumor microenvironment and the properties of NKTR-255 translated into superior antitumor activity in a B-cell lymphoma model versus the precomplexed cytokine.ConclusionsOur results show that the novel immunotherapeutic, NKTR-255, retains the full spectrum of IL-15 biology, but with improved PK properties, over rhIL-15. These findings support the ongoing phase 1 first-in-human trial (NCT04136756) of NKTR-255 in participants with relapsed or refractory hematologic malignancies, potentially advancing rhIL-15-based immunotherapies for the treatment of cancer.
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Adhami, Faisal, Jason C. Steel, and John Charles Morris. "Interleukin-15 expression in lung cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e21064-e21064. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e21064.

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e21064 Background: Interleukin-15 (IL-15) is a pro-inflammatory cytokine that stimulates the differentiation and proliferation of T, B, and NK cells. IL-15 is normally tightly bound by its receptor, IL-15Rα. Dendritic cells and monocytes/macrophages primarily express both IL-15 and IL-15-Rα; however, expression has been detected on epithelial cells including those of the lung. In the lung, IL-15 is thought to play a role in the induction of immune responses to infection. Over expression of IL-15 has been shown to induce NK cell activation and cytotoxic T-lymphocyte (CTL) responses leading to tumor regression. Little is known about IL-15 or IL-15Rα expression in lung cancer. Methods: mRNA from 146 primary lung cancers were analyzed by multiplex qPCR for expression of IL-15, IL-15Rα and b-actin (internal control) and compared to expression in normal lung tissue from 45 patients. Of the 146 patients, 50 were stage I (IA=20, IB=30), 49 stage II (IIA=9, IIB=40), 36 stage III (IIIA=18, IIIB=18), and 11 stage IV. Results: Comparing the expression of IL-15 between normal lung and tumor, we found tumors expressed significantly less IL-15 than normal lung (P<0.001). Lung cancers at any given stage, expressed significantly less IL-15 than that seen in normal lung. When comparing stages, stage IV tumors expressed significantly less IL-15 than tumors of stages I (P=0.021), II (P=0.020), or III (P=0.024). There was no difference in expression between stages I, II or III (P>0.05). When examining the expression of IL-15Rα we found no differences between normal lung and tumor. No differences were seen between normal lung and stages I-IIIA; however, significantly less IL-15Rα expression was noted in stages IIIB and IV compared to normal lung. Between stages, stages I and II had significantly more IL-15Rα expression than stage IV tumors. There were no differences between stages I, II and III. Conclusions: Pro-inflammatory cytokines such as IL-15 may be important for the induction of lung immunity. IL-15 expression is down regulated in lung cancers and this down regulation increases with stage. We posit that the down regulation of IL-15 by lung cancers may aid in their evasion of immune responses allowing progression and dissemination of tumor.
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Fiore, Piera Filomena, Sabina Di Matteo, Nicola Tumino, Francesca Romana Mariotti, Gabriella Pietra, Selene Ottonello, Simone Negrini, et al. "Interleukin-15 and cancer: some solved and many unsolved questions." Journal for ImmunoTherapy of Cancer 8, no. 2 (November 2020): e001428. http://dx.doi.org/10.1136/jitc-2020-001428.

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Soluble interleukin (IL)-15 exists under two forms: as monomer (sIL-15) or as heterodimeric complex in association with sIL-15Rα (sIL-15/IL-15Rα). Both forms have been successfully tested in experimental tumor murine models and are currently undergoing investigation in phase I/II clinical trials. Despite more than 20 years research on IL-15, some controversial issues remain to be addressed. A first point concerns the detection of the sIL-15/IL-15Rα in plasma of healthy donors or patients with cancer and its biological significance. The second and third unsolved question regards the protumorigenic role of the IL-15/IL-15Rα complex in human cancer and the detrimental immunological consequences associated to prolonged exposure of natural killer (NK) cells to both forms of soluble IL-15, respectively. Data suggest that in vivo prolonged or repeated exposure to monomeric sIL-15 or the soluble complex may lead to NK hypo-responsiveness through the expansion of the CD8+/CD44+ T cell subset that would suppress NK cell functions. In vitro experiments indicate that soluble complex and monomeric IL-15 may cause NK hyporesponsiveness through a direct effect caused by their prolonged stimulation, suggesting that this mechanism could also be effective in vivo. Therefore, a better knowledge of IL-15 and a more appropriate use of both its soluble forms, in terms of concentrations and time of exposure, are essential in order to improve their therapeutic use. In cancer, the overproduction of sIL-15/IL-15Rα could represent a novel mechanism of immune escape. The soluble complex may act as a decoy cytokine unable to efficiently foster NK cells, or could induce NK hyporesponsiveness through an excessive and prolonged stimulation depending on the type of IL-15Rα isoforms associated. All these unsolved questions are not merely limited to the knowledge of IL-15 pathophysiology, but are crucial also for the therapeutic use of this cytokine. Therefore, in this review, we will discuss key unanswered issues on the heterogeneity and biological significance of IL-15 isoforms, analyzing both their cancer-related biological functions and their therapeutic implications.
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Cole, David J., and Mark P. Rubinstein. "Soluble IL-15/IL-15Rα complexes in human serum." Blood 120, no. 1 (July 5, 2012): 1–2. http://dx.doi.org/10.1182/blood-2012-04-425306.

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27

Chirifu, Mami, Chiharu Hayashi, Teruya Nakamura, Sachiko Toma, Tsuyoshi Shuto, Hirofumi Kai, Yuriko Yamagata, Simon J. Davis, and Shinji Ikemizu. "23 Crystal Structure of IL-15/IL-15Rα Complex." Cytokine 39, no. 1 (July 2007): 7. http://dx.doi.org/10.1016/j.cyto.2007.07.028.

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28

Hasan, Aisha, Annamalai Selvakumar, Bo Dupont, Michel Sadelain, Isabelle Riviere, and Richard J. O’Reilly. "IL-15 Augments in-Vitro Expansion and Functional Activity of Antigen-Specific Effector Memory T-Cells (TEM) While Co-Expression of IL-15 and IL-15 Rα on Antigen Presenting Cells Also Promotes Expansion of Central Memory T-Cells (TCM)." Blood 112, no. 11 (November 16, 2008): 3541. http://dx.doi.org/10.1182/blood.v112.11.3541.3541.

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Abstract Adoptive immunotherapy with in-vitro expanded antigen-specific T cells (TC) is often hampered by the extended culture times required to generate sufficient numbers of antigen- specific TC and their limited persistence in-vivo. IL-2 predominantly supports the generation of short-lived effector memory (TEM) and effector (TE) CD8+ TC without expanding the CD62L+ and CCR7+ central memory T cells (TCM), which may persist for long periods in vivo. We examined the potential of IL-15 to foster growth of CMVpp65- specific TC as well as expansion of both TEM and TCM CD8+ TC. Accordingly, TC from 3 seropositive donors bearing HLA A0201 were sensitized in-vitro using NIH 3T3 based artificial antigen presenting cells transduced to express B7.1, ICAM-1, LFA-3, β2-M and HLA A0201 heavy chain as well as CMVpp65 (A2-AAPC) in presence of exogenous IL-2, IL-15 or IL-15 plus IL-2. To assess if trans-presentation of IL-15 by the receptor alpha on AAPCs leads to enhancement of IL-15 activity, we sequentially transduced A2-AAPCs with the IL-15 and IL-15 receptor alpha cDNA (A2- AAPC IL-15/IL-15Rα). TC were then cultured using A2-AAPC with either IL-2 (20U/ml) IL-15 (10ng/ml) IL-2 plus IL-15 or with A2-AAPC IL-15/IL-15Rα or A2-AAPC IL-15Rα + IL-2 (20U/ml). TC sensitized using either A2-AAPC IL-15/IL-15Rα or A2-AAPC + IL-15 demonstrated ~ 1500–2000 fold expansion of CMVpp65 A2-NLV tetramer (+) CD8+ TC, compared to a 300–600 fold expansion using A2-AAPC + IL-2 after 21–28 days in culture. Cultures containing IL-15 generated 25–70 ×106 A2-NLV tetramer (+) CD8+ TC in comparison to 10–18 ×106 in cultures with IL-2. At 7–10 days, ~20% of the tetramer (+) TC demonstrated a TCM phenotype (CD62L+ and CCR7+) in all cultures, with 75% TEM and 5% TE. By 21- 28 days, no TCM were detected among tetramer (+) TC in cultures containing exogenous IL-2, IL-15 or IL-2 plus IL-15. However, TC sensitized with A2-AAPC IL-15/IL-15Rα still contained 10–12% (~7×106) tetramer (+) CD8+ TCM which further increased through day 35. In functional assays, TC sensitized in the presence of IL-15 or AAPCs expressing IL-15 and IL-15Rα elicited superior CMV-specific responses with 7–20% CD8+ TC demonstrating CMVpp65 epitope specific interferon gamma production compared to 2–3% in cultures with IL-2. Cytotoxic activity against CMV pp65 peptide loaded autologous EBV transformed B-cell lines (E:T= 10:1) was higher for TC sensitized with IL-15 (80%) compared to cultures with IL-2 (60%). The cytotoxic activity against HLA mismatched targets or K562 was <5% in all cultures. In conclusion, our data demonstrate higher yields and augmented function in antigen specific T cells cultured with IL-15. TC sensitized with A2-AAPC-CMVpp65 together with IL-15 +/− IL-2 only supported sustained expansion of TEM and TE. In contrast, TC sensitized with A2-AAPC IL-15/IL-15Rα also supported sustained expansion of TCM.
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O'Connell, Grant, Ge Guo, Janelle Stricker, LeBris S. Quinn, Averil Ma, and Emidio E. Pistilli. "Muscle-specific deletion of exons 2 and 3 of theIL15RAgene in mice: effects on contractile properties of fast and slow muscles." Journal of Applied Physiology 118, no. 4 (February 15, 2015): 437–48. http://dx.doi.org/10.1152/japplphysiol.00704.2014.

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Interleukin-15 (IL-15) is a putative myokine hypothesized to induce an oxidative skeletal muscle phenotype. The specific IL-15 receptor alpha subunit (IL-15Rα) has also been implicated in specifying this contractile phenotype. The purposes of this study were to determine the muscle-specific effects of IL-15Rα functional deficiency on skeletal muscle isometric contractile properties, fatigue characteristics, spontaneous cage activity, and circulating IL-15 levels in male and female mice. Muscle creatine kinase (MCK)-driven IL-15Rα knockout mice ( mIl15rafl/fl/Cre+) were generated using the Cre-loxP system. We tested the hypothesis that IL-15Rα functional deficiency in skeletal muscle would increase resistance to contraction-induced fatigue, cage activity, and circulating IL-15 levels. There was a significant effect of genotype on the fatigue curves obtained in extensor digitorum longus (EDL) muscles from female mIl15rafl/fl/Cre+mice, such that force output was greater during the repeated contraction protocol compared with mIl15rafl/fl/Cre−control mice. Muscles from female mIl15rafl/fl/Cre+mice also had a twofold greater amount of the mitochondrial genome-specific COXII gene compared with muscles from mIl15rafl/fl/Cre−control mice, indicating a greater mitochondrial density in these skeletal muscles. There was a significant effect of genotype on the twitch:tetanus ratio in EDL and soleus muscles from mIl15rafl/fl/Cre+mice, such that the ratio was lower in these muscles compared with mIl15rafl/fl/Cre−control mice, indicating a pro-oxidative shift in muscle phenotype. However, spontaneous cage activity was not different and IL-15 protein levels were lower in male and female mIl15rafl/fl/Cre+mice compared with control. Collectively, these data support a direct effect of muscle IL-15Rα deficiency in altering contractile properties and fatigue characteristics in skeletal muscles.
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Escudero-Hernández, Celia, Beatriz Martínez-Abad, Violeta Ruipérez, José A. Garrote, and Eduardo Arranz. "New IL-15 receptor-α splicing variants identified in intestinal epithelial Caco-2 cells." Innate Immunity 23, no. 1 (October 28, 2016): 44–53. http://dx.doi.org/10.1177/1753425916674263.

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IL-15 is a pleiotropic cytokine related to IL-2 which acts at a broader level than its counterpart. It is presented through its specific high-affinity receptor, IL-15Rα. Both cytokine and receptor are tightly regulated at multiple levels and are widely distributed. Thus, deregulation of their expression leads to an inflammatory immune response. Variants of splicing of IL-15Rα have been described in immune and barrier cells; however, their presence has not been focused on intestinal epithelial cells. In this study, we describe five new alternative variants of splicing of IL-15Rα in Caco-2 cells. Four of them were expressed into proteins inside Caco-2 cells, but these were unable to bind IL-15 or to follow the secretory pathway. However, the expression of mRNA itself might be relevant to diseases such as celiac disease, inflammatory bowel disease or colorectal cancer.
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Bosch, Naomi C., Lena-Marie Martin, Caroline J. Voskens, Carola Berking, Barbara Seliger, Gerold Schuler, Niels Schaft, and Jan Dörrie. "A Chimeric IL-15/IL-15Rα Molecule Expressed on NFκB-Activated Dendritic Cells Supports Their Capability to Activate Natural Killer Cells." International Journal of Molecular Sciences 22, no. 19 (September 23, 2021): 10227. http://dx.doi.org/10.3390/ijms221910227.

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Natural killer (NK) cells, members of the innate immune system, play an important role in the rejection of HLA class I negative tumor cells. Hence, a therapeutic vaccine, which can activate NK cells in addition to cells of the adaptive immune system might induce a more comprehensive cellular response, which could lead to increased tumor elimination. Dendritic cells (DCs) are capable of activating and expanding NK cells, especially when the NFκB pathway is activated in the DCs thereby leading to the secretion of the cytokine IL-12. Another prominent NK cell activator is IL-15, which can be bound by the IL-15 receptor alpha-chain (IL-15Rα) to be transpresented to the NK cells. However, monocyte-derived DCs do neither secrete IL-15, nor express the IL-15Rα. Hence, we designed a chimeric protein consisting of IL-15 and the IL-15Rα. Upon mRNA electroporation, the fusion protein was detectable on the surface of the DCs, and increased the potential of NFκB-activated, IL-12-producing DC to activate NK cells in an autologous cell culture system with ex vivo-generated cells from healthy donors. These data show that a chimeric IL-15/IL-15Rα molecule can be expressed by monocyte-derived DCs, is trafficked to the cell surface, and is functional regarding the activation of NK cells. These data represent an initial proof-of-concept for an additional possibility of further improving cellular DC-based immunotherapies of cancer.
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Khan, Imtiaz A., Magali Moretto, Xiao-qing Wei, Martha Williams, Joseph D. Schwartzman, and Foo Y. Liew. "Treatment with Soluble Interleukin-15Rα Exacerbates Intracellular Parasitic Infection by Blocking the Development of Memory CD8+ T Cell Response." Journal of Experimental Medicine 195, no. 11 (June 3, 2002): 1463–70. http://dx.doi.org/10.1084/jem.20011915.

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Interferon (IFN)-γ–producing CD8+ T cells are important for the successful resolution of the obligate intracellular parasite Toxoplasma gondii by preventing the reactivation or controlling a repeat infection. Previous reports from our laboratory have shown that exogenous interleukin (IL)-15 treatment augments the CD8+ T cell response against the parasite. However, the role of endogenous IL-15 in the proliferation of activated/memory CD8+ T cells during toxoplasma or any other infection is unknown. In this study, we treated T. gondii immune mice with soluble IL-15 receptor α (sIL-15Rα) to block the host endogenous IL-15. The treatment markedly reduced the ability of the immune animals to control a lethal infection. CD8+ T cell activities in the sIL-15Rα–administered mice were severely reduced as determined by IFN-γ release and target cell lysis assays. The loss of CD8+ T cell immunity due to sIL-15Rα treatment was further demonstrated by adoptive transfer experiments. Naive recipients transferred with CD44hi activated/memory CD8+ T cells and treated with sIL-15Rα failed to resist a lethal T. gondii infection. Moreover, sIL-15Rα treatment of the recipients blocked the ability of donor CD44hi activated/memory CD8+ T cells to replicate in response to T. gondii challenge. To our knowledge, this is the first demonstration of the important role of host IL-15 in the development of antigen-specific memory CD8+ T cells against an intracellular infection.
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33

Chirifu, M., C. Hayashi, T. Nakamura, S. Toma, T. Shuto, H. Kai, Y. Yamagata, S. Davis, and S. Ikemizu. "Crystal structure of the human IL-15/IL-15Rα complex." Acta Crystallographica Section A Foundations of Crystallography 64, a1 (August 23, 2008): C317. http://dx.doi.org/10.1107/s010876730808985x.

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Stoklasek, Thomas A., Kimberly S. Schluns, and Leo Lefrançois. "Combined IL-15/IL-15Rα Immunotherapy Maximizes IL-15 Activity In Vivo." Journal of Immunology 177, no. 9 (October 18, 2006): 6072–80. http://dx.doi.org/10.4049/jimmunol.177.9.6072.

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35

Shirley, Shawna A., Cathryn G. Lundberg, and Richard Heller. "Electrotransfer of IL-15/IL-15Rα Complex for the Treatment of Established Melanoma." Cancers 12, no. 10 (October 21, 2020): 3072. http://dx.doi.org/10.3390/cancers12103072.

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Gene electrotransfer (GET) is a safe, reliable, and effective method of delivering plasmid DNA (pDNA) to solid tumors. GET has been previously used to deliver interleukin-15 (IL-15) to mouse melanoma, resulting in long-term tumor regression and the survival of a percentage of treated animals after challenge. To enhance this effect, we evaluated modulating the expression levels of IL-15 and co-expressing its receptor, IL-15Rα. GET was used to deliver plasmids encoding IL-15 and IL-15Rα to established B16.F10 tumors on days 0, 4, and 7. Two delivery protocols that yielded different expression profiles were utilized. Mice that were tumor-free for 50 days were then challenged with B16.F10 cells on the opposite flank and monitored for an additional 50 days. The amount of IL-15 expressed and the presence or absence of IL-15Rα in the treated tumors did not significantly affect the tumor regression and long-term survival. Upon challenge, however, low levels of IL-15 were more protective and resulted in a greater production of anti-tumor cytokines such as IFN-γ and MIP-1β and a greater amount of CD11b+ and CD3e+ cells infiltrating tumors. While mice with high levels of IL-15 showed CD11b+ and CD3e+ cell infiltrate, there was a substantial presence of NK cells that was absent in other treated groups. We can conclude that the level of IL-15 expressed in tumors after GET is an important determinant of the therapeutic outcome, a finding that will help us finetune this type of therapy.
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Beilin, Chiara, Kaushik Choudhuri, Gerben Bouma, Dessislava Malinova, Jaime Llodra, David L. Stokes, Motumu Shimaoka, et al. "Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse." Wellcome Open Research 3 (July 17, 2018): 84. http://dx.doi.org/10.12688/wellcomeopenres.14493.1.

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Background:Mutations of the common cytokine receptor gamma chain (γc) cause Severe Combined Immunodeficiency characterized by absent T and NK cell development. Although stem cell therapy restores these lineages, residual immune defects are observed that may result from selective persistence of γc-deficiency in myeloid lineages. However, little is known about the contribution of myeloid-expressed γc to protective immune responses. Here we examine the importance of γc for myeloid dendritic cell (DC) function.Methods:We utilize a combination ofin vitroDC/T-cell co-culture assays and a novel lipid bilayer system mimicking the T cell surface to delineate the role of DC-expressed γc during DC/T-cell interaction.Results:We observed that γc in DC was recruited to the contact interface following MHCII ligation, and promoted IL-15Rα colocalization with engaged MHCII. Unexpectedly, trans-presentation of IL-15 was required for optimal CD4+T cell activation by DC and depended on DC γc expression. Neither recruitment of IL-15Rα nor IL-15 trans-signaling at the DC immune synapse (IS), required γc signaling in DC, suggesting that γc facilitates IL-15 transpresentation through induced intermolecularcisassociations or cytoskeletal reorganization following MHCII ligation.Conclusions:These findings show that DC-expressed γc is required for effective antigen-induced CD4+ T cell activation. We reveal a novel mechanism for recruitment of DC IL-15/IL-15Rα complexes to the IS, leading to CD4+ T cell costimulation through localized IL-15 transpresentation that is coordinated with antigen-recognition.
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Beilin, Chiara, Kaushik Choudhuri, Gerben Bouma, Dessislava Malinova, Jaime Llodra, David L. Stokes, Motumu Shimaoka, et al. "Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse." Wellcome Open Research 3 (October 17, 2018): 84. http://dx.doi.org/10.12688/wellcomeopenres.14493.2.

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Background:Mutations of the common cytokine receptor gamma chain (γc) cause Severe Combined Immunodeficiency characterized by absent T and NK cell development. Although stem cell therapy restores these lineages, residual immune defects are observed that may result from selective persistence of γc-deficiency in myeloid lineages. However, little is known about the contribution of myeloid-expressed γc to protective immune responses. Here we examine the importance of γc for myeloid dendritic cell (DC) function.Methods:We utilize a combination ofin vitroDC/T-cell co-culture assays and a novel lipid bilayer system mimicking the T cell surface to delineate the role of DC-expressed γc during DC/T-cell interaction.Results:We observed that γc in DC was recruited to the contact interface following MHCII ligation, and promoted IL-15Rα colocalization with engaged MHCII. Unexpectedly, trans-presentation of IL-15 was required for optimal CD4+T cell activation by DC and depended on DC γc expression. Neither recruitment of IL-15Rα nor IL-15 trans-signaling at the DC immune synapse (IS), required γc signaling in DC, suggesting that γc facilitates IL-15 transpresentation through induced intermolecularcisassociations or cytoskeletal reorganization following MHCII ligation.Conclusions:These findings show that DC-expressed γc is required for effective antigen-induced CD4+ T cell activation. We reveal a novel mechanism for recruitment of DC IL-15/IL-15Rα complexes to the IS, leading to CD4+ T cell costimulation through localized IL-15 transpresentation that is coordinated with antigen-recognition.
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38

Suthaus, Jan, Anna Tillmann, Inken Lorenzen, Elena Bulanova, Stefan Rose-John, and Jürgen Scheller. "Forced Homo- and Heterodimerization of All gp130-Type Receptor Complexes Leads to Constitutive Ligand-independent Signaling and Cytokine-independent Growth." Molecular Biology of the Cell 21, no. 15 (August 2010): 2797–807. http://dx.doi.org/10.1091/mbc.e10-03-0240.

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Naturally ligand independent constitutively active gp130 variants were described to be responsible for inflammatory hepatocellular adenomas. Recently, we genetically engineered a ligand-independent constitutively active gp130 variant based on homodimerization of Jun leucine zippers. Because also heterodimeric complexes within the gp130 family may have tumorigenic potential, we seek to generate ligand-independent constitutively active heterodimers for all known gp130-receptor complexes based on IL-15/IL-15Rα-sushi fusion proteins. Ligand-independent heterodimerization of gp130 with WSX-1, LIFR, and OSMR and of OSMR with GPL led to constitutive, ligand-independent STAT1 and/or STAT3 and ERK1/2 phosphorylation. Moreover, these receptor combinations induced transcription of the STAT3 target genes c-myc and Pim-1 and factor-independent growth of stably transduced Ba/F3-gp130 cells. Here, we establish the IL-15/IL-15Rα-sushi system as a new system to mimic constitutive and ligand-independent activation of homo- and heterodimeric receptor complexes, which might be applicable to other heterodimeric receptor families. A mutated IL-15 protein, which was still able to bind the IL-15Rα-sushi domain, but not to β- and γ-receptor chains, in combination with the 2A peptide technology may be used to translate our in vitro data into the in vivo situation to assess the tumorigenic potential of gp130-heterodimeric receptor complexes.
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39

Quinn, LeBris S., Barbara G. Anderson, Jennifer D. Conner, Tami Wolden-Hanson, and Taylor J. Marcell. "IL-15 Is Required for Postexercise Induction of the Pro-Oxidative Mediators PPARδ and SIRT1 in Male Mice." Endocrinology 155, no. 1 (January 1, 2014): 143–55. http://dx.doi.org/10.1210/en.2013-1645.

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Physical exercise induces transient upregulation of the pro-oxidative mediators peroxisome proliferator-activated receptor-δ (PPARδ), silent information regulator of transcription (sirtuin)-1 (SIRT1), PPARγ coactivator 1α (PGC-1α), and PGC-1β in skeletal muscle. To determine the role of the cytokine IL-15 in acute postexercise induction of these molecules, expression of these factors after a bout of exhaustive treadmill running was examined in the gastrocnemius muscle of untrained control and IL-15–knockout (KO) mice. Circulating IL-15 levels increased transiently in control mice after exercise. Control mice, but not IL-15–KO mice, upregulated muscle PPARδ and SIRT1 protein after exercise, accompanied by a complex pattern of mRNA expression for these factors. However, in exhaustive exercise, control mice ran significantly longer than IL-15–KO mice. Therefore, in a second experiment, mice were limited to a 20-minute run, after which a similar pattern of induction of muscle PPARδ and SIRT1 protein by control mice only was observed. In a separate experiment, IL-15–KO mice injected systemically with recombinant IL-15 upregulated muscle PPARδ and SIRT1 mRNA within 30 minutes and also exhibited increased muscle PPARδ protein levels by 3 hours. After exercise, both control and IL-15–KO mice downregulated IL-15 receptor-α (IL-15Rα) mRNA, whereas IL-15Rα–deficient mice exhibited constitutively elevated circulating IL-15 levels. These observations indicate IL-15 release after exercise is necessary for induction of PPARδ and SIRT1 at the protein level in muscle tissue and suggest that exercise releases IL-15 normally sequestered by the IL-15Rα in the resting state. These findings could be used to develop an IL-15–based strategy to induce many of the metabolic benefits of physical exercise.
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40

Giron-Michel, Julien, Fanny Menard, Simone Negrini, Aurore Devocelle, Bruno Azzarone, and Caroline Besson. "EBV-associated mononucleosis does not induce long-term global deficit in T-cell responsiveness to IL-15." Blood 113, no. 19 (May 7, 2009): 4541–47. http://dx.doi.org/10.1182/blood-2008-12-195289.

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Abstract It has been reported that infectious mononucleosis (IM)–symptomatic primary Epstein-Barr virus infection produces a global down-regulation of interleukin-15 receptor-α (IL-15Rα) on T cells and natural killer cells associated with a defective IL-15 responsiveness that lasts for many years after the disease episode. In contrast with these results, our data indicate that, in the T-cell compartment derived from remote IM subjects, there is no quantitative or qualitative defect in the expression of the IL-15Rα chain and no deficit in T-cell responsiveness to IL-15. We observed efficient signal transduction, survival, and proliferation even in response to low IL-15 concentrations. These data are relevant and shed new light on the immune long-term response in IM subjects because they contradict the hypothesis that defects in Epstein-Barr virus–host immune balance may be correlated with a long-lasting global deficit in T-cell responsiveness to IL-15.
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41

Dubois, Sigrid, Jennifer Mariner, Thomas A. Waldmann, and Yutaka Tagaya. "IL-15Rα Recycles and Presents IL-15 In trans to Neighboring Cells." Immunity 17, no. 5 (November 2002): 537–47. http://dx.doi.org/10.1016/s1074-7613(02)00429-6.

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42

Xiao, Run, Anthony G. Mansour, Wei Huang, Logan A. Chrislip, Ryan K. Wilkins, Nicholas J. Queen, Youssef Youssef, Hsiaoyin C. Mao, Michael A. Caligiuri, and Lei Cao. "Adipocytes: A Novel Target for IL-15/IL-15Rα Cancer Gene Therapy." Molecular Therapy 27, no. 5 (May 2019): 922–32. http://dx.doi.org/10.1016/j.ymthe.2019.02.011.

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43

Escudero-Hernández, Celia, Leticia Plaza-Izurieta, José A. Garrote, José Ramón Bilbao, and Eduardo Arranz. "Association of the IL-15 and IL-15Rα genes with celiac disease." Cytokine 99 (November 2017): 73–79. http://dx.doi.org/10.1016/j.cyto.2017.07.009.

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44

Bouchaud, Grégory, Laure Garrigue-Antar, Véronique Solé, Agnès Quéméner, Yvan Boublik, Erwan Mortier, Harmonie Perdreau, Yannick Jacques, and Ariane Plet. "The Exon-3-Encoded Domain of IL-15Rα Contributes to IL-15 High-Affinity Binding and Is Crucial for the IL-15 Antagonistic Effect of Soluble IL-15Rα." Journal of Molecular Biology 382, no. 1 (September 2008): 1–12. http://dx.doi.org/10.1016/j.jmb.2008.07.019.

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45

Islam, S. M. Shamsul, Bunsoon Choi, Juyoung Choi, Eun-So Lee, and Seonghyang Sohn. "Frequencies of IL-15Rα+ cells in patients with Behçet’s disease and the effects of overexpressing IL-15Rα+ on disease symptoms in mice." Cytokine 110 (October 2018): 257–66. http://dx.doi.org/10.1016/j.cyto.2018.01.010.

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46

Kobayashi, Hisataka, Sigrid Dubois, Noriko Sato, Helen Sabzevari, Yoshio Sakai, Thomas A. Waldmann, and Yutaka Tagaya. "Role of trans-cellular IL-15 presentation in the activation of NK cell–mediated killing, which leads to enhanced tumor immunosurveillance." Blood 105, no. 2 (January 15, 2005): 721–27. http://dx.doi.org/10.1182/blood-2003-12-4187.

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AbstractInterleukin 15 (IL-15) is a critical factor for the proliferation and activation of natural killer (NK) and CD8 T cells. Recently, we demonstrated that IL-15Rα expressed on monocytes/dendritic cells captures and presents IL-15 to neighboring cells in trans (trans-presentation of IL-15) through cell-cell contact. In the current study, we provide evidence that the IL-15 presented in trans, but not soluble IL-15 at physiologic concentrations, augments the killing activity mediated by NK cells in vitro. In addition, transfection of IL-15Rα into a colon carcinoma cell line (MC38) enabled these cells to present IL-15 in trans to NK cells and augmented their killing activity, resulting in the efficient lysis of MC38 cells by NK cells in vitro. Furthermore, these transfected MC38 cells no longer form fatal pulmonary metastases in mice. It was also shown that NK cells play an important role in the rejection of MC38 cells under these circumstances. These results collectively suggest that the IL-15 trans-presentation mechanism operates in vivo to augment the tumor immune surveillance mechanism. Furthermore, our observation provides the scientific basis for a novel strategy to prevent cancer development/metastasis.
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47

Romee, Rizwan, Sarah Cooley, Melissa M. Berrien-Elliott, Peter Westervelt, Michael R. Verneris, John E. Wagner, Daniel J. Weisdorf, et al. "First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation." Blood 131, no. 23 (June 7, 2018): 2515–27. http://dx.doi.org/10.1182/blood-2017-12-823757.

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Key Points Single-agent IL-15/IL-15Rα-Fc (ALT-803) therapy was well tolerated and resulted in clinical responses in patients who relapsed post-HCT. First-in-human use of ALT-803 promoted NK and CD8+ T-cell expansion and activation in vivo without stimulating regulatory T cells.
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48

Kumar, Rajesh, Sanjeev Kumar, D. P. Singh, and Priyanka Gaur. "DNA Polymorphism at IL-2Rγ and IL-15Rα Genes in Aseel Native chicken." Journal of Applied Animal Research 32, no. 1 (September 2007): 107–10. http://dx.doi.org/10.1080/09712119.2007.9706857.

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49

Pérez-López, A., J. McKendry, M. Martin-Rincon, D. Morales-Alamo, B. Pérez-Köhler, D. Valadés, J. Buján, J. A. L. Calbet, and L. Breen. "Skeletal muscle IL-15/IL-15Rα and myofibrillar protein synthesis after resistance exercise." Scandinavian Journal of Medicine & Science in Sports 28, no. 1 (May 26, 2017): 116–25. http://dx.doi.org/10.1111/sms.12901.

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50

Bergamaschi, Cristina, Brunda Ganneru, Margherita Rosati, Osamu Usami, Antonio Valentin, Rachel K. Beach, Candido Alicea, Barbara K. Felber, and George N. Pavlakis. "PL4-4 Heterodimeric IL-15/IL-15Rα accelerates immune reconstitution in lymphopenic mice." Cytokine 52, no. 1-2 (October 2010): 100. http://dx.doi.org/10.1016/j.cyto.2010.07.424.

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