IL-15Rα Recycles and Presents IL-15 In trans to Neighboring Cells
TL;DR: These complexes on activated monocytes present IL-15 in trans to target cells such as CD8 + T cells that express only IL-2/15Rβ and γc upon cell-cell interaction and contribute to the long survival of T cells expressing IL- 15Rα afterIL-15 withdrawal.
About: This article is published in Immunity.The article was published on 2002-11-01 and is currently open access. It has received 874 citations till now. The article focuses on the topics: Interleukin 15.
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TL;DR: These key transcription factors T-bet and eomesodermin link the long-term renewal of memory CD8+ T cells to their characteristic effector potency, and are responsible for inducing enhanced expression of CD122, the receptor specifying interleukin 15 responsiveness.
Abstract: Two seemingly unrelated hallmarks of memory CD8(+) T cells are cytokine-driven proliferative renewal after pathogen clearance and a latent effector program in anticipation of rechallenge. Memory CD8(+) T cells and natural killer cells share cytotoxic potential and dependence on the growth factor interleukin 15. We now show that mice with compound mutations of the genes encoding the transcription factors T-bet and eomesodermin were nearly devoid of several lineages dependent on interleukin 15, including memory CD8(+) T cells and mature natural killer cells, and that their cells had defective cytotoxic effector programming. Moreover, T-bet and eomesodermin were responsible for inducing enhanced expression of CD122, the receptor specifying interleukin 15 responsiveness. Therefore, these key transcription factors link the long-term renewal of memory CD8(+) T cells to their characteristic effector potency.
1,151 citations
TL;DR: This review highlights recent advances in how naive and memory T cell homeostasis is regulated.
1,102 citations
Cites background from "IL-15Rα Recycles and Presents IL-15..."
...The requirement for SLO appears to be because, as with IL-2 and IL-15 (Dubois et al., 2002; Wrenshall and Platt, 1999), IL-7 is probably displayed largely in cell-associated form at the site of production, bound to the extracellular matrix, instead of being distributed systemically in soluble form....
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...However, the physiological relevance of this finding is questionable because AgSp CD4+ T cells were generated and studied in gc-deficient hosts, which harbor unphysiologically high amounts of IL-2 and IL-15; these cytokines are now known to induce strong activation of CD4+ and CD8+ T cells and this response can be further augmented by contact with self-MHC molecules (Cho et al., 2007; Ramsey et al., 2008)....
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...In this regard, IL-2 and IL-15 seem to transmit much stronger proliferative and differentiation signals than does IL-7....
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...Cellular presentation of IL-15 was first directly demonstrated with human cell lines and then confirmed in the mouse by the finding that IL-15 activity in vivo required synthesis and expression of IL-15 and IL-15Ra by the same cell (Burkett et al., 2004; Dubois et al., 2002; Sandau et al., 2004)....
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...For this reason, production of IL-2 and IL-15 in vivo is probably tightly controlled in order to prevent unintended activation of bystander naive T cells during a strong immune response to pathogenic microbes....
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TL;DR: The biology of these cytokines will affect the development of novel therapies for malignancy and autoimmune diseases, as well as the design of vaccines against infectious diseases.
Abstract: Interleukin-2 and interleukin-15 have pivotal roles in the control of the life and death of lymphocytes. Although their heterotrimeric receptors have two receptor subunits in common, these two cytokines have contrasting roles in adaptive immune responses. The unique role of interleukin-2 is in the elimination of self-reactive T cells to prevent autoimmunity. By contrast, interleukin-15 is dedicated to the prolonged maintenance of memory T-cell responses to invading pathogens. As discussed in this Review, the biology of these cytokines will affect the development of novel therapies for malignancy and autoimmune diseases, as well as the design of vaccines against infectious diseases.
1,018 citations
Cites background from "IL-15Rα Recycles and Presents IL-15..."
...It induces signalling in the context of cell–cell contact; at the immunological synapse , signals from the IL-15R are delivered together with co-stimulatory signals that modify the response of the cel...
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TL;DR: Inhibitory receptors for major histocompatibility complex class I (MHC-I) have a critical role in controlling NK cell responses and, paradoxically, in maintaining NK cells in a state of responsiveness to subsequent activation events, a process referred to as licensing.
Abstract: Understanding how signals are integrated to control natural killer (NK) cell responsiveness in the absence of antigen-specific receptors has been a challenge, but recent work has revealed some underlying principles that govern NK cell responses. NK cells use an array of innate receptors to sense their environment and respond to alterations caused by infections, cellular stress, and transformation. No single activation receptor dominates; instead, synergistic signals from combinations of receptors are integrated to activate natural cytotoxicity and cytokine production. Inhibitory receptors for major histocompatibility complex class I (MHC-I) have a critical role in controlling NK cell responses and, paradoxically, in maintaining NK cells in a state of responsiveness to subsequent activation events, a process referred to as licensing. MHC-I-specific inhibitory receptors both block activation signals and trigger signals to phosphorylate and inactivate the small adaptor Crk. These different facets of inhibito...
980 citations
TL;DR: The findings suggest that the current methodology for selecting T cells for transfer is inadequate and provide new criteria for the generation and the screening of optimal lymphocyte populations for adoptive immunotherapy.
Abstract: T cell differentiation is a progressive process characterized by phenotypic and functional changes. By transferring tumor-specific CD8+ T cells into tumor-bearing mice at various stages of differentiation, we evaluated their efficacy for adoptive immunotherapy. We found that administration of naive and early effector T cells, in combination with active immunization and IL-2, resulted in the eradication of large, established tumors. Despite enhanced in vitro antitumor properties, more-differentiated effector T cells were less effective for in vivo tumor treatment. Several events may underlie this paradoxical phenomenon: (a) downregulation of lymphoid-homing and costimulatory molecules; (b) inability to produce IL-2 and access homeostatic cytokines; and (c) entry into a proapoptotic and replicative senescent state. While the progressive acquisition of terminal effector properties is characterized by pronounced in vitro tumor killing, in vivo T cell activation, proliferation, and survival are progressively impaired. These findings suggest that the current methodology for selecting T cells for transfer is inadequate and provide new criteria for the generation and the screening of optimal lymphocyte populations for adoptive immunotherapy.
914 citations
References
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TL;DR: Critical roles for IL-15 in the development of specific lymphoid lineages are revealed and the ability to rescue lymphoid defects inIL-15−/− mice by IL- 15 administration represents a powerful means by which to further elucidate the biological roles of this cytokine.
Abstract: C57BL/6 mice genetically deficient in interleukin 15 (IL-15−/− mice) were generated by gene targeting. IL-15−/− mice displayed marked reductions in numbers of thymic and peripheral natural killer (NK) T cells, memory phenotype CD8+ T cells, and distinct subpopulations of intestinal intraepithelial lymphocytes (IELs). The reduction but not absence of these populations in IL-15−/− mice likely reflects an important role for IL-15 for expansion and/or survival of these cells. IL-15−/− mice lacked NK cells, as assessed by both immunophenotyping and functional criteria, indicating an obligate role for IL-15 in the development and functional maturation of NK cells. Specific defects associated with IL-15 deficiency were reversed by in vivo administration of exogenous IL-15. Despite their immunological defects, IL-15−/− mice remained healthy when maintained under specific pathogen-free conditions. However, IL-15−/− mice are likely to have compromised host defense responses to various pathogens, as they were unable to mount a protective response to challenge with vaccinia virus. These data reveal critical roles for IL-15 in the development of specific lymphoid lineages. Moreover, the ability to rescue lymphoid defects in IL-15−/− mice by IL-15 administration represents a powerful means by which to further elucidate the biological roles of this cytokine.
1,586 citations
TL;DR: IL-15Ralpha has pleiotropic roles in immune development and function, including the positive maintenance of lymphocyte homeostasis, and is generated in mice deficient in natural killer cells, natural killer T cells, CD8+ T lymphocytes, and TCRgammadelta intraepithelial lymphocytes.
1,303 citations
TL;DR: It is shown here that, unlike IL-2, IL-15 closely mimics the effects of IFN I in causing strong and selective stimulation of memory-phenotype CD44hi CD8+ (but not CD4+) cells in vivo; similar specificity applies to purified T cells in vitro and correlates with much higher expression of IL- 2Rbeta onCD8+ cells than on CD4+ cells.
1,281 citations
TL;DR: Interleukin-2 receptor alpha chain expression occurs at specific stages of early T and B lymphocyte development and is induced upon activation of mature lymphocytes, probably by influencing the balance between clonal expansion and cell death following lymphocyte activation.
1,091 citations
TL;DR: A functional analysis of recombinant IL-15 on phenotypically and functionally distinct populations of highly purified human natural killer (NK) cells revealed the presence of high and intermediate affinity receptors for both ligands.
Abstract: Interleukin 15 (IL-15) is a novel cytokine that has recently been cloned and expressed. Whereas it has no sequence homology with IL-2, IL-15 interacts with components of the IL-2 receptor (IL-2R). In the present study we performed a functional analysis of recombinant IL-15 on phenotypically and functionally distinct populations of highly purified human natural killer (NK) cells. The CD56bright subset of human NK cells constitutively expresses the high affinity IL-2R and exhibits a brisk proliferative response after the binding of picomolar amounts of IL-2. Using a proliferation assay, IL-15 demonstrated a very steep dose-response curve that was distinct from the dose-response curve for IL-2. The proliferative effects of IL-15 could be abrogated by anti-IL-2R beta (p75), but not by anti-IL-2R alpha (p55). The proliferative effects of IL-2 on CD56bright NK cells could be inhibited by both antibodies. CD56dim NK cells express the intermediate affinity IL-2R in the absence of the high affinity IL-2R. Activation of CD56dim NK cells by IL-15 was similar to that of IL-2 as measured by enhanced NK cytotoxic activity, antibody-dependent cellular cytotoxicity, and NK cell production of interferon gamma, tumor necrosis factor alpha, and granulocyte/macrophage colony-stimulating factor. The IL-15-enhanced NK cytotoxic activity could be completely blocked by anti-IL-2R beta monoclonal antibody. The binding of radiolabeled IL-2 and IL-15 to CD56dim NK cells was inhibited in the presence of anti-IL-2R beta. Scatchard analysis of radiolabeled IL-15 and IL-2 binding to NK-enriched human lymphocytes revealed the presence of high and intermediate affinity receptors for both ligands. IL-15 is a ligand that activates human NK cells through components of the IL-2R in a pattern that is similar but not identical to that of IL-2. Unlike IL-2, IL-15 is produced by activated monocytes/macrophages. The discovery of IL-15 may increase our understanding of how monocytes/macrophages participate in the regulation of NK cell function.
1,079 citations