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• W2470258189 abstract "•The γc cytokines interleukin (IL)-2, IL-7, and IL-15 regulate immune cell differentiation.•IL-2, IL-7, and IL-15 modulate naïve, effector, and memory CD4+ T-cell function.•Despite similarities in signaling pathways, these γc cytokines have unique functions.•IL-2, IL-7, and IL-15 signaling pathways are targets of immunotherapeutic strategies. Cytokines represent a class of environmental factors that are critical drivers of immune cell development. Cytokines of the common gamma-chain family, including interleukin (IL)-2, IL-7, and IL-15, have been the subject of intense experimental scrutiny and have well-defined roles as regulators of diverse immune cell types including CD4+ T helper cells. Because of their pleiotropic effects on T-cell development and function, researchers and clinicians have attempted to harness the capabilities of these cytokines for therapeutic benefit. In this review, we summarize the recent progress in our understanding of the molecular mechanisms underlying the effects of these cytokines on CD4+ T cell development and briefly discuss how these immunomodulatory cytokines are being used in efforts to treat human disease. Cytokines represent a class of environmental factors that are critical drivers of immune cell development. Cytokines of the common gamma-chain family, including interleukin (IL)-2, IL-7, and IL-15, have been the subject of intense experimental scrutiny and have well-defined roles as regulators of diverse immune cell types including CD4+ T helper cells. Because of their pleiotropic effects on T-cell development and function, researchers and clinicians have attempted to harness the capabilities of these cytokines for therapeutic benefit. In this review, we summarize the recent progress in our understanding of the molecular mechanisms underlying the effects of these cytokines on CD4+ T cell development and briefly discuss how these immunomodulatory cytokines are being used in efforts to treat human disease. CD4+ T helper cells are critical for the generation of effective immunity to a multitude of pathogens as they supply secreted factors and engage in aspects of cell-to-cell signaling to promote comprehensive immune responses. A number of distinct CD4+ T helper subsets have been described, including T helper 1 (TH1), TH2, TH9, TH17, TH22, T follicular helper (TFH), and regulatory T cell (TREG) populations, with each performing unique functions that are required for pathogen clearance, humoral immunity, and immune tolerance [1Kaplan M.H. Hufford M. Olson M.R. The development and in vivo function of T helper 9 cells.Nat Rev Immunol. 2015; 15: 295-307Crossref PubMed Scopus (178) Google Scholar, 2Ma C.S. Deenick E.K. Batten M. Tangye S.G. The origins, function, and regulation of T follicular helper cells.J Exp Med. 2012; 209: 1241-1253Crossref PubMed Scopus (304) Google Scholar, 3Reinhardt R.L. Kang S.J. Liang H.E. Locksley R.M. T helper cell effector fates—Who, how and where?.Curr Opin Immunol. 2006; 18: 271-277Crossref PubMed Scopus (0) Google Scholar, 4Zhu J. Yamane H. Paul W.E. Differentiation of effector CD4 T cell populations.Annu Rev Immunol. 2010; 28: 445-489Crossref PubMed Scopus (1626) Google Scholar, 5Basu R. Hatton R.D. Weaver C.T. The Th17 family: Flexibility follows function.Immunol Rev. 2013; 252: 89-103Crossref PubMed Scopus (147) Google Scholar]. For example, TH1 and TH2 cells play key roles in mediating immunity to intracellular pathogens and extracellular parasites, respectively, whereas TH17 cells are primary contributors to mucosal immunity [5Basu R. Hatton R.D. Weaver C.T. The Th17 family: Flexibility follows function.Immunol Rev. 2013; 252: 89-103Crossref PubMed Scopus (147) Google Scholar, 6Zhu J. Paul W.E. CD4 T cells: Fates, functions and faults.Blood. 2008; 112: 1557-1569Crossref PubMed Scopus (0) Google Scholar]. TFH cells, an additional subset, are required for effective humoral immune responses as they provide help to B cells to promote germinal center formation and antibody production [7Crotty S.T. T follicular helper cell differentiation function and roles in disease.Immunity. 2014; 41: 529-542Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 8Vinuesa C.G. Linterman M.A. Yu D. MacLennan I.C. Follicular helper T cells.Annu Rev Immunol. 2016; 34: 335-368Crossref PubMed Scopus (310) Google Scholar]. Finally, TREG cells are responsible for properly regulating the effector responses of the cells described above to avoid potential autoimmunity and maintain areas of immunologic privilege [9Josefowicz S.Z. Lu L.F. Rudensky A.Y. Regulatory T cells: mechanisms of differentiation and function.Annu Rev Immunol. 2012; 30: 531-564Crossref PubMed Scopus (1382) Google Scholar]. Recently, an emerging body of evidence supports the concept that a degree of flexibility exists between these subsets, leading to the understanding that activated T helper cells can transition from one cell type to another based, in large part, on alterations to the cytokine environment [5Basu R. Hatton R.D. Weaver C.T. The Th17 family: Flexibility follows function.Immunol Rev. 2013; 252: 89-103Crossref PubMed Scopus (147) Google Scholar, 10Bonelli M. Shih H.I. Hirahara K. et al.Helper T cell plasticity: impact of extrinsic and intrinsic signals on transcriptomes and epigenomes.Curr Top Microbiol Immunol. 2014; 381: 279-326PubMed Google Scholar, 11Geginat J. Paroni M. Magli S. et al.Plasticity of human CD4 T cell subsets.Front Immunol. 2014; 5: 630Crossref PubMed Scopus (100) Google Scholar, 12Zhou L. Chong M.M. Littman D.R. Plasticity of CD4+ T cell lineage differentiation.Immunity. 2009; 30: 646-655Abstract Full Text Full Text PDF PubMed Scopus (924) Google Scholar]. This review explores the differential roles of the cytokines interleukin (IL)-2, IL-7, and IL-15 in the regulation of T helper cell subset specification and the potential flexibility between CD4+ T cell populations. We also highlight current immunotherapeutic strategies that target these cytokine pathways in an effort to capitalize on the phenomenon of T helper cell plasticity to treat a variety of disease states. IL-2 is a 15.4-kDa cytokine that was first discovered in the supernatant of stimulated lymphocyte cultures as a necessary factor for T cell differentiation and long-term survival [13Morgan D.A. Ruscetti F.W. Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows.Science. 1976; 193: 1007-1008Crossref PubMed Google Scholar]. IL-2 signaling is mediated through a three-subunit IL-2 receptor complex, which includes IL-2 receptor alpha (IL-2Rα or CD25), IL-2 receptor beta (IL-2Rβ or CD122), and the common gamma (γc) chain. Although all three receptors can participate in different subunit complexes, high-affinity binding/signaling is achieved through the IL-2Rα/β/γc trimeric form of receptor [14Liao W. Lin J.X. Leonard W.J. IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation.Curr Opin Immunol. 2011; 23: 598-604Crossref PubMed Scopus (317) Google Scholar, 15Liao W. Lin J.X. Leonard W.J. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy.Immunity. 2013; 38: 13-25Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar]. In the absence of IL-2Rα, an IL-2Rβ/γc dimer is also capable of forming an intermediate-affinity binding complex. IL-2 receptor complexes signal via three main pathways, including the Janus kinase/signal transducer and activator of transcription (Jak/STAT), phosphatidylinositol-3-kinase (PI3K)-AKT, and SHC-RAS-mitogen-activated protein kinase (MAPK) pathways [15Liao W. Lin J.X. Leonard W.J. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy.Immunity. 2013; 38: 13-25Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar, 16Malek T.R. Castro I. Interleukin-2 receptor signaling: At the interface between tolerance and immunity.Immunity. 2010; 33: 153-165Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar]. Activation of the receptor complex by IL-2 results in activation of Jak1 and Jak3, which associate with IL-2Rβ and γc, respectively. After Jak1/3 activation, subsequent differential tyrosine phosphorylation events of the IL-2Rβ cytoplasmic domain result in activation of the Jak/STAT, PI3K-AKT, and SHC-RAS-MAPK signaling pathways. The STAT transcription factors activated by IL-2 include STAT1, STAT3, and STAT5A/B, with STAT5 signaling predominating during high-affinity IL-2 binding [15Liao W. Lin J.X. Leonard W.J. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy.Immunity. 2013; 38: 13-25Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar]. After their phosphorylation, STAT factors dimerize and translocate to the nucleus, where they bind and regulate transcriptional activation or repression of target genes. The role of IL-2 in CD4+ T cell biology has expanded from a simple T cell growth factor to include both activation and inhibition of specific T helper cell types. These effects, described in greater detail below, appear to be both concentration and timing dependent, indicating that changing IL-2 concentrations can favor one cell type over another at specific times during immune cell development. Although IL-2 was initially established as an essential cytokine for CD4+ T cell proliferation and expansion, murine neonates deficient for IL-2 displayed massive lymphocyte proliferation and developed severe autoimmunity, implicating IL-2 in the development of self-tolerance [17Sadlack B. Löhler J. Schorle H. et al.Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells.Eur J Immunol. 1995; 25: 3053-3059Crossref PubMed Scopus (325) Google Scholar, 18Sadlack B. Merz H. Schorle H. Schimpl A. Feller A.C. Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene.Cell. 1993; 75: 253-261Abstract Full Text PDF PubMed Scopus (1443) Google Scholar]. Consistent with these findings, subsequent studies revealed that IL-2 signaling in the thymus results in the expansion of TREG cells, which downregulate T helper cell effector functions and potential autoimmune responses [19Malek T.R. Yu A. Vincek V. Scibelli P. Kong L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice: Implications for the nonredundant function of IL-2.Immunity. 2002; 17: 167-178Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. The surprising finding that a growth factor required for T cell proliferation was also necessary for limiting T cell expansion and autoimmunity has been largely explained by both the timing of IL-2 exposure (i.e., during thymic selection vs. after activation) and the concentration of IL-2 to which the cells are exposed (low dose for TREG survival vs. high dose for infection-specific effector expansion). Interestingly, TREG cells can also be induced outside of the thymus when naïve T cells are exposed to transforming growth factor β (TGF-β) and IL-2 [20Davidson T.S. DiPaolo R.J. Andersson J. Shevach E.M. Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells.J Immunol. 2007; 178: 4022-4026Crossref PubMed Google Scholar, 21Zheng S.G. Wang J. Wang P. Gray J.D. Horwitz D.A. IL-2 is essential for TGF-beta to convert naive CD4+CD25− cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells.J Immunol. 2007; 178: 2018-2027Crossref PubMed Google Scholar]. These induced TREGS (iTREGS) are found in mucosa, chronically inflamed tissue, and the gastrointestinal tract, where iTreg cells are thought to mediate normal immune responses to commensal bacteria and food antigens [22Izcue A. Powrie F. Special regulatory T-cell review: Regulatory T cells and the intestinal tract—Patrolling the frontier.Immunology. 2008; 123: 6-10Crossref PubMed Scopus (0) Google Scholar]. Outside of the thymus, naïve T cell activation via MHCII antigen presentation and subsequent IL-2 signaling primes CD4+ T cells for a variety of effector functions. Interestingly, IL-2 is a powerful regulator of T helper cell differentiation in part because of its differential effects on cytokine receptor expression (Fig. 1). A series of elegant studies by Leonard et al. revealed that IL-2 signaling promotes the development of both TH1 and TH2 cell types by inducing expression of IL-12Rβ2 and IL-4Rα, respectively [23Liao W. Lin J.X. Wang L. Li P. Leonard W.J. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages.Nat Immunol. 2011; 12: 551-555Crossref PubMed Scopus (239) Google Scholar, 24Liao W. Schones D.E. Oh J. et al.Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression.Nat Immunol. 2008; 9: 1288-1296Crossref PubMed Scopus (164) Google Scholar]. Conversely, IL-2 has been reported to suppress TH17 development through repression of the IL-6R signaling complex and STAT5-dependent inhibition of IL-17 expression [23Liao W. Lin J.X. Wang L. Li P. Leonard W.J. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages.Nat Immunol. 2011; 12: 551-555Crossref PubMed Scopus (239) Google Scholar, 25Laurence A. Tato C.M. Davidson T.S. et al.Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation.Immunity. 2007; 26: 371-381Abstract Full Text Full Text PDF PubMed Scopus (996) Google Scholar]. Thus, IL-2 acts to broadly regulate T helper cell differentiation, at least in part, by inducing or repressing the expression of specific cytokine receptors and signaling pathways. IL-2 signaling has also been found to inhibit the formation of particular T helper cell subsets through the repression of subset-specific “lineage-defining” transcription factors. Specifically, numerous studies have indicated an inverse relationship between IL-2 signaling and expression of the transcriptional repressor Bcl-6 [26Johnston R.J. Choi Y.S. Diamond J.A. Yang J.A. Crotty S. STAT5 is a potent negative regulator of TFH cell differentiation.J Exp Med. 2012; 209: 243-250Crossref PubMed Scopus (282) Google Scholar, 27Nurieva R.I. Podd A. Chen Y. et al.STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function.J Biol Chem. 2012; 287: 11234-11239Crossref PubMed Scopus (137) Google Scholar, 28Oestreich K.J. Mohn S.E. Weinmann A.S. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile.Nat Immunol. 2012; 13: 405-411Crossref PubMed Scopus (196) Google Scholar, 29Pepper M. Pagan A.J. Igyarto B.Z. Taylor J.J. Jenkins M.K. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells.Immunity. 2011; 35: 583-595Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 30Pipkin M.E. Sacks J.A. Cruz-Guilloty F. Lichtenheld M.G. Bevan M.J. Rao A. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells.Immunity. 2010; 32: 79-90Abstract Full Text Full Text PDF PubMed Scopus (410) Google Scholar]. Bcl-6 has been identified as the lineage-defining transcription factor for the development of CD4+ TFH cells, which interact with B cells to assist in antibody affinity maturation and production in germinal center reactions during the course of infection [7Crotty S.T. T follicular helper cell differentiation function and roles in disease.Immunity. 2014; 41: 529-542Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 31Johnston R.J. Poholek A.C. DiToro D. et al.Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation.Science. 2009; 325: 1006-1010Crossref PubMed Scopus (872) Google Scholar, 32Nurieva R.I. Chung Y. Martinez G.J. et al.Bcl6 mediates the development of T follicular helper cells.Science. 2009; 325: 1001-1005Crossref PubMed Scopus (831) Google Scholar, 33Yu D. Rao S. Tsai L.M. et al.The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment.Immunity. 2009; 31: 457-468Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar]. Indeed, mice receiving high levels of IL-2 during influenza infection display reduced TFH and germinal center formation, indicating that increased IL-2 signaling disrupts TFH formation in vivo [34Ballesteros-Tato A. Leon B. Graf B.A. et al.Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation.Immunity. 2012; 36: 847-856Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar]. Mechanistically, it has been reported that direct binding of IL-2-activated STAT5 to the Bcl6 locus inhibits the expression of Bcl-6 and the TFH gene program (Fig. 2) [26Johnston R.J. Choi Y.S. Diamond J.A. Yang J.A. Crotty S. STAT5 is a potent negative regulator of TFH cell differentiation.J Exp Med. 2012; 209: 243-250Crossref PubMed Scopus (282) Google Scholar, 27Nurieva R.I. Podd A. Chen Y. et al.STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function.J Biol Chem. 2012; 287: 11234-11239Crossref PubMed Scopus (137) Google Scholar, 28Oestreich K.J. Mohn S.E. Weinmann A.S. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile.Nat Immunol. 2012; 13: 405-411Crossref PubMed Scopus (196) Google Scholar]. Interestingly, in TH1 cells, a reduction of IL-2 signaling correlates with increased Bcl-6 expression and the induction of a TFH-like gene program. Thus, potential plasticity between the TH1 and TFH cell types is regulated, in part, by alterations in IL-2 signaling and Bcl-6 expression [28Oestreich K.J. Mohn S.E. Weinmann A.S. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile.Nat Immunol. 2012; 13: 405-411Crossref PubMed Scopus (196) Google Scholar]. Flexibility with the TFH cell fate may not be limited to TH1 cells, as it has been found that TH2 and TH17 cells are similarly capable of upregulating TFH-like gene profiles [35Lu K.T. Kanno Y. Cannons J.L. et al.Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells.Immunity. 2011; 35: 622-632Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar]. Future work is necessary to determine if there is an analogous role for IL-2 signaling in the regulation of TH2-TFH and TH17-TFH plasticity. Similar to TFH cells, CD4+ memory T cell formation is dependent on Bcl-6 expression [29Pepper M. Pagan A.J. Igyarto B.Z. Taylor J.J. Jenkins M.K. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells.Immunity. 2011; 35: 583-595Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 36Ichii H. Sakamoto A. Arima M. Hatano M. Kuroda Y. Tokuhisa T. Bcl6 is essential for the generation of long-term memory CD4+ T cells.Int Immunol. 2007; 19: 427-433Crossref PubMed Scopus (50) Google Scholar]. As such, it is unsurprising that IL-2 signaling has also been implicated in the repression of memory cell formation. Initially in CD8+ T cells, and later in CD4+ T cells, IL-2 signaling was reported to inhibit the expression of many memory-associated genes, including Bcl-6 [28Oestreich K.J. Mohn S.E. Weinmann A.S. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile.Nat Immunol. 2012; 13: 405-411Crossref PubMed Scopus (196) Google Scholar, 30Pipkin M.E. Sacks J.A. Cruz-Guilloty F. Lichtenheld M.G. Bevan M.J. Rao A. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells.Immunity. 2010; 32: 79-90Abstract Full Text Full Text PDF PubMed Scopus (410) Google Scholar, 37McDonald P.W. Read K.A. Baker C.E. et al.IL-7 signalling represses Bcl-6 and the TFH gene program.Nat Commun. 2016; 7: 10285Crossref PubMed Google Scholar]. Furthermore, it is well established that memory cells have decreased cell surface expression of IL-2Rα, which is consistent with a repressive role for IL-2 in memory cell formation [29Pepper M. Pagan A.J. Igyarto B.Z. Taylor J.J. Jenkins M.K. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells.Immunity. 2011; 35: 583-595Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 37McDonald P.W. Read K.A. Baker C.E. et al.IL-7 signalling represses Bcl-6 and the TFH gene program.Nat Commun. 2016; 7: 10285Crossref PubMed Google Scholar, 38Gasper D.J. Tejera M.M. Suresh M. CD4 T-cell memory generation and maintenance.Crit Rev Immunol. 2014; 34: 121-146Crossref PubMed Scopus (0) Google Scholar, 39McKinstry K.K. Golech S. Lee W.H. et al.Rapid default transition of CD4 T cell effectors to functional memory cells.J Exp Med. 2007; 204: 2199-2211Crossref PubMed Scopus (74) Google Scholar]. Thus, IL-2 signaling appears to exploit the common requirement for Bcl-6 to repress both TFH and memory cell gene programs. In a recent study, we found that in response to reduced IL-2 signaling and T cell receptor (TCR) stimulation, TH1 cells co-initiate the expression of Bcl-6-dependent TFH and TCM gene programs [37McDonald P.W. Read K.A. Baker C.E. et al.IL-7 signalling represses Bcl-6 and the TFH gene program.Nat Commun. 2016; 7: 10285Crossref PubMed Google Scholar]. We propose that a potential continuum may exist between the TH1, TFH, and TCM cell types, with changes in these cellular programs regulated by the IL-2 signaling/Bcl-6 expression axis discussed previously. Our interpretation is that this transition may allow a subset of post-effector TH1 cells to engage in aspects of both long-term humoral and cell-mediated immunity [37McDonald P.W. Read K.A. Baker C.E. et al.IL-7 signalling represses Bcl-6 and the TFH gene program.Nat Commun. 2016; 7: 10285Crossref PubMed Google Scholar]. Interestingly, despite the considerable evidence supporting a role for IL-2 in the negative regulation of some memory cell gene programs, it should be noted that there are reports of an IL-2 requirement for the development of tissue-resident memory (TRM) cells, suggesting that differential effects of IL-2 signaling on memory cell populations may also be population and stage specific [40McKinstry K.K. Strutt T.M. Bautista B. et al.Effector CD4 T-cell transition to memory requires late cognate interactions that induce autocrine IL-2.Nat Commun. 2014; 5: 5377Crossref PubMed Scopus (57) Google Scholar, 41Hondowicz B.D. An D. Schenkel J.M. et al.Interleukin-2-dependent allergen-specific tissue-resident memory cells drive asthma.Immunity. 2016; 44: 155-166Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar]. IL-7 is a 20.2-kDa cytokine that was first discovered as a novel growth factor responsible for promoting the proliferation of murine B cell precursors in a long-term bone marrow culture system, and has since been found to be essential for lymphocyte development and survival [42Namen A.E. Schmierer A.E. March C.J. et al.B cell precursor growth-promoting activity: Purification and characterization of a growth factor active on lymphocyte precursors.J Exp Med. 1988; 167: 988-1002Crossref PubMed Google Scholar, 43Ceredig R. Rolink A.G. The key role of IL-7 in lymphopoiesis.Semin Immunol. 2012; 24: 159-164Crossref PubMed Scopus (0) Google Scholar]. Following IL-7 binding to IL-7R, the γc receptor is recruited to form a high-affinity binding complex, which signals through the Jak1/Jak3/STAT5 and PI3K-AKT signaling pathways [44Carrette F. Surh C.D. IL-7 signaling and CD127 receptor regulation in the control of T cell homeostasis.Semin Immunol. 2012; 24: 209-217Crossref PubMed Scopus (109) Google Scholar, 45Kondo M. Takeshita T. Higuchi M. et al.Functional participation of the IL-2 receptor gamma chain in IL-7 receptor complexes.Science. 1994; 263: 1453-1454Crossref PubMed Google Scholar]. These pathways are shared with IL-2, despite each cytokine harboring unique roles in the regulation of immune system development and function [46Katzman S.D. Hover K.K. Dooms H. et al.Opposing functions of IL-2 and IL-7 in the regulation of immune responses.Cytokine. 2011; 56: 116-121Crossref PubMed Scopus (0) Google Scholar]. 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Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine.J Exp Med. 1995; 181: 1519-1526Crossref PubMed Scopus (1161) Google Scholar]. This includes decreased T cell numbers in the lymph nodes and spleen, which suggest a nonredundant role for IL-7 in mediating the development and survival of CD4+ T cells [47Peschon J.J. Morrissey P.J. Grabstein K.H. et al.Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice.J Exp Med. 1994; 180: 1955-1960Crossref PubMed Scopus (1226) Google Scholar, 49Puel A. Ziegler S.F. Buckley R.H. Leonard W.J. Defective IL7R expression in T(−)B(+)NK(+) severe combined immunodeficiency.Nat Genet. 1998; 20: 394-397Crossref PubMed Scopus (607) Google Scholar, 50von Freeden-Jeffry U. Vieira P. Lucian L.A. McNeil T. Burdach S.E. Murray R. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine.J Exp Med. 1995; 181: 1519-1526Crossref PubMed Scopus (1161) Google Scholar]. Naïve CD4+ T helper cells are critically dependent on IL-7 for their homeostasis and, thus, display increased cell surface expression of IL-7R. Interestingly, upon IL-7/IL-7R engagement, cells downregulate the expression of the receptor [51Park J.H. Yu Q. Erman B. et al.Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival.Immunity. 2004; 21: 289-302Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar]. As IL-7 is present only in small quantities in vivo, this is likely a beneficial regulatory phenomenon, because it allows a maximal number of naïve cells to be exposed to a limited amount of cytokine. Following activation, naïve CD4+ T cells downregulate IL-7R, transition to the effector CD4+ T cell stage, and receive survival signals from TCR stimulation in addition to other environmental factors including IL-2 [52Xue H.H. Kovanen P.E. Pise-Masison C.E. et al.IL-2 negatively regulates IL-7 receptor alpha chain expression in activated T lymphocytes.Proc Natl Acad Sci U S A. 2002; 99: 13759-13764Crossref PubMed Scopus (132) Google Scholar]. During the effector-to-memory transition, post-effector CD4+ T cells upregulate IL-7R expression and again rely on IL-7 for homeostasis [38Gasper D.J. Tejera M.M. Suresh M. CD4 T-cell memory generation and maintenance.Crit Rev Immunol. 2014; 34: 121-146Crossref PubMed Scopus (0) Google Scholar]. Although a role for IL-7 in the survival of memory cell populations is well established, emerging evidence supports the existence of additional IL-7-dependent regulatory mechanisms. Two recent studies reported that an antagonistic relationship exists between IL-7 signaling and Bcl-6 expression [37McDonald P.W. Read K.A. Baker C.E. et al.IL-7 signalling represses Bcl-6 and the TFH gene program.Nat Commun. 2016; 7: 10285Crossref PubMed Google Scholar, 53Liu X. Lu H. Chen T. et al.Genome-wide analysis identifies Bcl6-controlled regulatory networks during T follicular helper cell differentiation.Cell Rep. 2016; 14: 1735-1747Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar]. Similar to previous findings observed with IL-2 signaling, our laboratory discovered that signaling via the IL-7/STAT5 pathway inhibits Bcl-6 expression and several members of the TFH gene program [37McDonald P.W. Read K.A. Baker C.E. et al.IL-7 signalling represses Bcl-6 and the TFH gene program.Nat Commun. 2016; 7: 10285Crossref PubMed Google Scholar]. Surprisingly, IL-7 did not repress TCM gene expression patterns, despite the initial dependence of the TCM gene program on Bcl-6 expression. These data suggest that IL-7 may not only play a critical role in promoting memory cell survival but also may participate in regulating specific events associated with memory cell trafficking and function (Fig. 2). Additionally, these data are suggestive of the intriguing possibility that IL-7 may function to augment aspects of cellular metabolism, as Bcl-6 has been identified as a negative regulator of the glycolytic gene program [54Oestreich K.J. Read K.A. Gilbertson S.E. et al.Bcl-6 directly represses the gene program of the glycolysis pathway.Nat Immunol. 2014; 15: 957-964Crossref PubMed Scopus (92) Google Scholar]. Indeed, IL-7 was recently reported to induce expression of the glycerol channel aquap" @default.
• W2470258189 created "2016-07-22" @default.
• W2470258189 creator A5024656909 @default.
• W2470258189 creator A5045859168 @default.
• W2470258189 creator A5053205953 @default.
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• W2470258189 date "2016-09-01" @default.
• W2470258189 modified "2023-10-16" @default.
• W2470258189 title "IL-2, IL-7, and IL-15: Multistage regulators of CD4+ T helper cell differentiation" @default.
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