Key Points
-
The common cytokine receptor γ-chain (γc) family of cytokines consists of interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21, each of which is a short-chain four α-helical bundle type I cytokine. Mutations in the gene encoding γc (IL2RG) in humans result in X-linked severe combined immunodeficiency, which is characterized by a marked defect in the development of T and natural killer (NK) cells and functional defects of B cells; in mice, deletion of this gene is characterized by the absence of B, T and NK cells.
-
γc family cytokines and the related cytokine thymic stromal lymphopoietin (TSLP) have distinct effects on the regulation of survival and proliferation of T cells. IL-2 and TSLP increase the proliferation and/or survival of effector T cells, whereas IL-7, IL-15 and TSLP are survival factors for naive and memory αβ T cells, as well as γδ T cells. In addition, the combination of IL-15 and IL-21 increases the proliferation and decreases the apoptosis of CD8+ T cells.
-
As well as the direct effects of γc family cytokines and TSLP on the homeostasis of T cells, they also have indirect effects on T cells through their regulation of dendritic cell (DC) functions. IL-15 and TSLP induce the up-regulation of expression of co-stimulatory molecules and increased presentation of antigen on DCs, whereas IL-7 and IL-21 suppress the maturation of DCs.
-
Although IL-2 is an important factor for the development and function of regulatory T (TReg) cells, the lack of IL-2, IL-2Rα or IL-2Rβ does not alter the expression of forkhead box P3 (FOXP3) or result in a complete loss of TReg cells. By contrast, STAT5 activation is sufficient to increase the number of CD4+CD25+ TReg cells even when IL-2-induced signalling is defective, which shows that STAT5A and STAT5B are crucial factors downstream of IL-2R and indicates that other factors that activate the STAT5 pathway might also contribute to TReg cell development and could partially compensate when IL-2-induced signalling is defective. Indeed, IL-7, IL-15 and TSLP also contribute to TReg cell development and function.
-
In the primary response to antigen, naive CD4+ T cells differentiate to distinct polarized subsets, including T helper 1 (TH1), TH2, TH17 and T follicular helper (TFH) cells. Recent studies show that IL-2 and IL-4 are both required for the efficient induction of TH2 cells and that IL-21 can promote the differentiation of TH17 cells and TFH cells. In addition to their contributions to TH cell differentiation, γc cytokines also contribute to the generation and activity of cytotoxic CD8+ T cells, with IL-2, IL-15 and IL-21 increasing the cytolytic activity of CD8+ T cells during priming and increasing their antitumour immunity.
-
The actions of γc cytokines have clinical relevance, and modulation of their effects has implications for the treatment of cancer, autoimmunity, allergy and immunodeficiency. Administration of IL-2, IL-15 and IL-21 has antitumour effects; treatment with IL-2, IL-7 and IL-15 could be used in immunodeficiency disorders; blocking of IL-4, IL-9 and TSLP can decrease allergic symptoms; and neutralization of IL-21 could prevent and/or ameliorate several autoimmune diseases.
Abstract
Common cytokine receptor γ-chain (γc) family cytokines have crucial roles in the development, proliferation, survival and differentiation of multiple cell lineages of both the innate and adaptive immune systems. In this Review, we focus on our current understanding of the distinct and overlapping effects of interleukin-2 (IL-2), IL-7, IL-9, IL-15 and IL-21, as well as the IL-7-related cytokine thymic stromal lymphopoietin (TSLP), on the survival and proliferation of conventional αβ T cells, γδ T cells and regulatory T cells. This knowledge potentially allows for the therapeutic manipulation of immune responses for the treatment of cancer, autoimmunity, allergic diseases and immunodeficiency, as well as for vaccine development.
This is a preview of subscription content, access via your institution
Access options
Subscription info for Chinese customers
We have a dedicated website for our Chinese customers. Please go to naturechina.com to subscribe to this journal.
Buy this article
- Purchase on SpringerLink
- Instant access to the full article PDF.
39,95 €
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
References
Leonard, W. J. Cytokines and immunodeficiency diseases. Nature Rev. Immunol. 1, 200–208 (2001).
Spolski, R. & Leonard, W. J. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu. Rev. Immunol. 26, 57–79 (2008).
Takeshita, T. et al. Cloning of the γ chain of the human IL-2 receptor. Science 257, 379–382 (1992).
Wang, X., Lupardus, P., Laporte, S. L. & Garcia, K. C. Structural biology of shared cytokine receptors. Annu. Rev. Immunol. 27, 29–60 (2009). A comprehensive review that details the structures of cytokine receptor families that contain gp130, γ c or β c , highlights structural similarities and differences between these families, and discusses their abilities to bind ligands and mediate signalling.
Noguchi, M. et al. Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73, 147–157 (1993). This paper showed that mutations in IL2RG result in XSCID in humans and therefore revealed crucial roles for γ c in the development of T cells and NK cells. The authors correctly speculated that γ c has important roles beyond the action of IL-2.
Kim, H. P., Imbert, J. & Leonard, W. J. Both integrated and differential regulation of components of the IL-2/IL-2 receptor system. Cytokine Growth Factor Rev. 17, 349–366 (2006).
Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).
D'Souza, W. N. & Lefrancois, L. IL-2 is not required for the initiation of CD8 T cell cycling but sustains expansion. J. Immunol. 171, 5727–5735 (2003).
Lenardo, M. J. Interleukin-2 programs mouse αβ T lymphocytes for apoptosis. Nature 353, 858–861 (1991).
Holgate, S. T. & Polosa, R. Treatment strategies for allergy and asthma. Nature Rev. Immunol. 8, 218–230 (2008).
Macchi, P. et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377, 65–68 (1995).
Russell, S. M. et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 270, 797–800 (1995).
Puel, A., Ziegler, S. F., Buckley, R. H. & Leonard, W. J. Defective IL7R expression in T−B+NK+ severe combined immunodeficiency. Nature Genet. 20, 394–397 (1998).
Parrish, Y. K. et al. IL-7 dependence in human B lymphopoiesis increases during progression of ontogeny from cord blood to bone marrow. J. Immunol. 182, 4255–4266 (2009).
Mazzucchelli, R. & Durum, S. K. Interleukin-7 receptor expression: intelligent design. Nature Rev. Immunol. 7, 144–154 (2007).
Surh, C. D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848–862 (2008).
Veldhoen, M. et al. Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nature Immunol. 9, 1341–1346 (2008).
Dardalhon, V. et al. IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+IL-10+Foxp3− effector T cells. Nature Immunol. 9, 1347–1355 (2008).
Hauber, H. P., Bergeron, C. & Hamid, Q. IL-9 in allergic inflammation. Int. Arch. Allergy Immunol. 134, 79–87 (2004).
Uyttenhove, C., Simpson, R. J. & Van Snick, J. Functional and structural characterization of P40, a mouse glycoprotein with T-cell growth factor activity. Proc. Natl Acad. Sci. USA 85, 6934–6938 (1988).
Spolski, R., Kashyap, M., Robinson, C., Yu, Z. & Leonard, W. J. IL-21 signaling is critical for the development of type I diabetes in the NOD mouse. Proc. Natl Acad. Sci. USA 105, 14028–14033 (2008).
Datta, S. & Sarvetnick, N. E. IL-21 limits peripheral lymphocyte numbers through T cell homeostatic mechanisms. PLoS ONE 3, e3118 (2008).
Bubier, J. A. et al. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proc. Natl Acad. Sci. USA 106, 1518–1523 (2009). References 21–23 show that IL-21 has a crucial role in the pathogenesis of both organ-specific and systemic autoimmune diseases.
Leonard, W. J. & Spolski, R. Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nature Rev. Immunol. 5, 688–698 (2005).
Liu, Y. J. et al. TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu. Rev. Immunol. 25, 193–219 (2007).
Pandey, A. et al. Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin. Nature Immunol. 1, 59–64 (2000).
Park, L. S. et al. Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: formation of a functional heteromeric complex requires interleukin 7 receptor. J. Exp. Med. 192, 659–670 (2000).
Nakajima, H., Shores, E. W., Noguchi, M. & Leonard, W. J. The common cytokine receptor γ chain plays an essential role in regulating lymphoid homeostasis. J. Exp. Med. 185, 189–195 (1997). This was the first paper to show a crucial role for γ c in lymphocyte homeostasis.
Schluns, K. S., Kieper, W. C., Jameson, S. C. & Lefrancois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nature Immunol. 1, 426–432 (2000).
Goldrath, A. W. et al. Cytokine requirements for acute and basal homeostatic proliferation of naive and memory CD8+ T cells. J. Exp. Med. 195, 1515–1522 (2002).
Seddon, B., Tomlinson, P. & Zamoyska, R. Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells. Nature Immunol. 4, 680–686 (2003).
Sportes, C. et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J. Exp. Med. 205, 1701–1714 (2008).
Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nature Immunol. 8, 1255–1265 (2007).
Fry, T. J. & Mackall, C. L. The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance. J. Immunol. 174, 6571–6576 (2005).
Alves, N. L., van Leeuwen, E. M., Derks, I. A. & van Lier, R. A. Differential regulation of human IL-7 receptor α expression by IL-7 and TCR signaling. J. Immunol. 180, 5201–5210 (2008).
Xue, H. H. et al. IL-2 negatively regulates IL-7 receptor α chain expression in activated T lymphocytes. Proc. Natl Acad. Sci. USA 99, 13759–13764 (2002).
Park, J. H. et al. Suppression of IL7Rα transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity 21, 289–302 (2004). References 36 and 37 show that IL-2- and IL-7-induced signals negatively regulate the expression of IL-7Rα.
Xue, H. H. et al. GA binding protein regulates interleukin 7 receptor α-chain gene expression in T cells. Nature Immunol. 5, 1036–1044 (2004).
Chandele, A. et al. Formation of IL-7Rαhigh and IL-7Rαlow CD8 T cells during infection is regulated by the opposing functions of GABPα and Gfi-1. J. Immunol. 180, 5309–5319 (2008).
Tan, J. T. et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl Acad. Sci. USA 98, 8732–8737 (2001).
Min, B., Yamane, H., Hu-Li, J. & Paul, W. E. Spontaneous and homeostatic proliferation of CD4 T cells are regulated by different mechanisms. J. Immunol. 174, 6039–6044 (2005).
Al-Shami, A. et al. A role for thymic stromal lymphopoietin in CD4+ T cell development. J. Exp. Med. 200, 159–168 (2004).
Chappaz, S., Flueck, L., Farr, A. G., Rolink, A. G. & Finke, D. Increased TSLP availability restores T- and B-cell compartments in adult IL-7 deficient mice. Blood 110, 3862–3870 (2007).
Rochman, Y. & Leonard, W. J. The role of thymic stromal lymphopoietin in CD8+ T cell homeostasis. J. Immunol. 181, 7699–7705 (2008).
Ku, C. C., Murakami, M., Sakamoto, A., Kappler, J. & Marrack, P. Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288, 675–678 (2000).
Schluns, K. S., Williams, K., Ma, A., Zheng, X. X. & Lefrancois, L. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J. Immunol. 168, 4827–4831 (2002).
Berard, M., Brandt, K., Bulfone-Paus, S. & Tough, D. F. IL-15 promotes the survival of naive and memory phenotype CD8+ T cells. J. Immunol. 170, 5018–5026 (2003).
Judge, A. D., Zhang, X., Fujii, H., Surh, C. D. & Sprent, J. Interleukin 15 controls both proliferation and survival of a subset of memory-phenotype CD8+ T cells. J. Exp. Med. 196, 935–946 (2002).
Purton, J. F. et al. Antiviral CD4+ memory T cells are IL-15 dependent. J. Exp. Med. 204, 951–961 (2007).
Sandau, M. M., Winstead, C. J. & Jameson, S. C. IL-15 is required for sustained lymphopenia-driven proliferation and accumulation of CD8 T cells. J. Immunol. 179, 120–125 (2007).
Rubinstein, M. P. et al. Converting IL-15 to a superagonist by binding to soluble IL-15Rα. Proc. Natl Acad. Sci. USA 103, 9166–9171 (2006).
Stoklasek, T. A., Schluns, K. S. & Lefrancois, L. Combined IL-15/IL-15Rα immunotherapy maximizes IL-15 activity in vivo. J. Immunol. 177, 6072–6080 (2006).
Dubois, S., Mariner, J., Waldmann, T. A. & Tagaya, Y. IL-15Rα recycles and presents IL-15 in trans to neighboring cells. Immunity 17, 537–547 (2002). This paper describes the formation of stable IL-15–IL-15Rα complexes on the cell surface that mediate trans -presentation of IL-15 and provide survival signals for target cells.
Burkett, P. R. et al. IL-15Rα expression on CD8+ T cells is dispensable for T cell memory. Proc. Natl Acad. Sci. USA 100, 4724–4729 (2003).
Zeng, R. et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J. Exp. Med. 201, 139–148 (2005). This paper describes the ability of IL-21 to act synergistically with other γ c family cytokines as a proliferative agent for CD8+ T cells in vitro and in vivo during an antitumour response.
Alves, N. L., Arosa, F. A. & van Lier, R. A. IL-21 sustains CD28 expression on IL-15-activated human naive CD8+ T cells. J. Immunol. 175, 755–762 (2005).
Ozaki, K. et al. A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630–1634 (2002).
Allard, E. L. et al. Overexpression of IL-21 promotes massive CD8+ memory T cell accumulation. Eur. J. Immunol. 37, 3069–3077 (2007).
Sojka, D. K., Bruniquel, D., Schwartz, R. H. & Singh, N. J. IL-2 secretion by CD4+ T cells in vivo is rapid, transient, and influenced by TCR-specific competition. J. Immunol. 172, 6136–6143 (2004).
Cote-Sierra, J. et al. Interleukin 2 plays a central role in Th2 differentiation. Proc. Natl Acad. Sci. USA 101, 3880–3885 (2004).
Liao, W. et al. Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor α-chain expression. Nature Immunol. 9, 1288–1296 (2008). References 60 and 61 show a central role of IL-2 in T H 2 cell differentiation. IL-2 activates STAT5, which binds to the Il4 and Il4ra loci and promotes their transcription.
Morgan, D. A., Ruscetti, F. W. & Gallo, R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 193, 1007–1008 (1976).
Blattman, J. N. et al. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nature Med. 9, 540–547 (2003).
Rubinstein, M. P. et al. IL-7 and IL-15 differentially regulate CD8+ T-cell subsets during contraction of the immune response. Blood 112, 3704–3712 (2008).
Mattei, F., Schiavoni, G., Belardelli, F. & Tough, D. F. IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J. Immunol. 167, 1179–1187 (2001).
Dubois, S. P., Waldmann, T. A. & Muller, J. R. Survival adjustment of mature dendritic cells by IL-15. Proc. Natl Acad. Sci. USA 102, 8662–8667 (2005).
Ohteki, T. et al. Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo. J. Exp. Med. 203, 2329–2338 (2006).
Yajima, T. et al. IL-15 regulates CD8+ T cell contraction during primary infection. J. Immunol. 176, 507–515 (2006).
Oh, S. et al. IL-15 as a mediator of CD4+ help for CD8+ T cell longevity and avoidance of TRAIL-mediated apoptosis. Proc. Natl Acad. Sci. USA 105, 5201–5206 (2008).
Kaech, S. M. et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nature Immunol. 4, 1191–1198 (2003).
Hand, T. W., Morre, M. & Kaech, S. M. Expression of IL-7 receptor α is necessary but not sufficient for the formation of memory CD8 T cells during viral infection. Proc. Natl Acad. Sci. USA 104, 11730–11735 (2007).
Haring, J. S. et al. Constitutive expression of IL-7 receptor α does not support increased expansion or prevent contraction of antigen-specific CD4 or CD8 T cells following Listeria monocytogenes infection. J. Immunol. 180, 2855–2862 (2008).
Klonowski, K. D., Williams, K. J., Marzo, A. L. & Lefrancois, L. Cutting edge: IL-7-independent regulation of IL-7 receptor α expression and memory CD8 T cell development. J. Immunol. 177, 4247–4251 (2006).
Lacombe, M. H., Hardy, M. P., Rooney, J. & Labrecque, N. IL-7 receptor expression levels do not identify CD8+ memory T lymphocyte precursors following peptide immunization. J. Immunol. 175, 4400–4407 (2005).
Rochman, I., Watanabe, N., Arima, K., Liu, Y. J. & Leonard, W. J. Cutting edge: direct action of thymic stromal lymphopoietin on activated human CD4+ T cells. J. Immunol. 178, 6720–6724 (2007). This was the first demonstration of a direct effect of TSLP on human T cells. TSLPR expression is increased by activated CD4+ T cells. TSLP binding to TSLPR promotes the activation of STAT5, which induces the upregulation of IL-2Rα expression and thereby increases the sensitivity of CD4+ T cells to IL-2.
Rochman, Y. & Leonard, W. J. Thymic stromal lymphopoietin: a new cytokine in asthma. Curr. Opin. Pharmacol. 8, 249–254 (2008).
Born, W. K., Reardon, C. L. & O'Brien, R. L. The function of γδ T cells in innate immunity. Curr. Opin. Immunol. 18, 31–38 (2006).
Jameson, J. & Havran, W. L. Skin γδ T-cell functions in homeostasis and wound healing. Immunol. Rev. 215, 114–122 (2007).
Baccala, R. et al. γδ T cell homeostasis is controlled by IL-7 and IL-15 together with subset-specific factors. J. Immunol. 174, 4606–4612 (2005).
French, J. D., Roark, C. L., Born, W. K. & O'Brien, R. L. γδ T cell homeostasis is established in competition with αβ T cells and NK cells. Proc. Natl Acad. Sci. USA 102, 14741–14746 (2005).
Laky, K., Lewis, J. M., Tigelaar, R. E. & Puddington, L. Distinct requirements for IL-7 in development of TCR γδ cells during fetal and adult life. J. Immunol. 170, 4087–4094 (2003).
Furtado, G. C., Curotto de Lafaille, M. A., Kutchukhidze, N. & Lafaille, J. J. Interleukin 2 signaling is required for CD4+ regulatory T cell function. J. Exp. Med. 196, 851–857 (2002).
Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nature Immunol. 6, 1142–1151 (2005). Using Il2−/− or Il2ra−/− mice, the authors show that IL-2 is important for maintaining the homeostasis of T Reg cells. Although IL-2 is not required for T Reg cell development, γ c -deficient mice are devoid of FOXP3+ T Reg cells. These data are consistent with the idea that more than one cytokine contributes to T Reg cell development and it is now clear that IL-2, IL-7 and TSLP are three such cytokines (see Refs 94,95).
Antony, P. A. et al. Interleukin-2-dependent mechanisms of tolerance and immunity in vivo. J. Immunol. 176, 5255–5266 (2006).
Bayer, A. L., Yu, A. & Malek, T. R. Function of the IL-2R for thymic and peripheral CD4+CD25+Foxp3+ T regulatory cells. J. Immunol. 178, 4062–4071 (2007).
Yao, Z. et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109, 4368–4375 (2007).
Antov, A., Yang, L., Vig, M., Baltimore, D. & Van Parijs, L. Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. J. Immunol. 171, 3435–3441 (2003).
Burchill, M. A., Yang, J., Vogtenhuber, C., Blazar, B. R. & Farrar, M. A. IL-2 receptor β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J. Immunol. 178, 280–290 (2007).
Cohen, A. C. et al. Cutting edge: decreased accumulation and regulatory function of CD4+CD25high T cells in human STAT5b deficiency. J. Immunol. 177, 2770–2774 (2006).
Lin, J. X. et al. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity 2, 331–339 (1995).
Lin, J. X., Mietz, J., Modi, W. S., John, S. & Leonard, W. J. Cloning of human Stat5B. Reconstitution of interleukin-2-induced Stat5A and Stat5B DNA binding activity in COS-7 cells. J. Biol. Chem. 271, 10738–10744 (1996).
Nakajima, H. et al. An indirect effect of Stat5a in IL-2-induced proliferation: a critical role for Stat5a in IL-2-mediated IL-2 receptor α chain induction. Immunity 7, 691–701 (1997).
Imada, K. et al. Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity. J. Exp. Med. 188, 2067–2074 (1998).
Mazzucchelli, R. et al. Development of regulatory T cells requires IL-7Rα stimulation by IL-7 or TSLP. Blood 112, 3283–3292 (2008). Whereas mice deficient in IL-7 or TSLPR have relatively normal numbers of T Reg cells, combined deficiency of IL-7 and TSLPR greatly decreases the number of T Reg cells, indicating that both IL-7 and TSLP contribute to T Reg cell development.
Bayer, A. L., Lee, J. Y., de la Barrera, A., Surh, C. D. & Malek, T. R. A function for IL-7R for CD4+CD25+Foxp3+ T regulatory cells. J. Immunol. 181, 225–234 (2008).
Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ TReg cells. J. Exp. Med. 203, 1701–1711 (2006).
Seddiki, N. et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693–1700 (2006).
Pandiyan, P. & Lenardo, M. J. The control of CD4+CD25+Foxp3+ regulatory T cell survival. Biol. Direct 3, 6 (2008).
Bayer, A. L., Yu, A., Adeegbe, D. & Malek, T. R. Essential role for interleukin-2 for CD4+CD25+ T regulatory cell development during the neonatal period. J. Exp. Med. 201, 769–777 (2005).
Zhang, H. et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nature Med. 11, 1238–1243 (2005).
Fukao, T. & Koyasu, S. Expression of functional IL-2 receptors on mature splenic dendritic cells. Eur. J. Immunol. 30, 1453–1457 (2000).
Mnasria, K. et al. Anti-CD25 antibodies affect cytokine synthesis pattern of human dendritic cells and decrease their ability to prime allogeneic CD4+ T cells. J. Leukocyte Biol. 84, 460–467 (2008).
Combe, C. L. et al. Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite. Proc. Natl Acad. Sci. USA 103, 6635–6640 (2006).
Moretto, M. M., Lawlor, E. M. & Khan, I. A. Aging mice exhibit a functional defect in mucosal dendritic cell response against an intracellular pathogen. J. Immunol. 181, 7977–7984 (2008).
Jinushi, M. et al. Autocrine/paracrine IL-15 that is required for type I IFN-mediated dendritic cell expression of MHC class I-related chain A and B is impaired in hepatitis C virus infection. J. Immunol. 171, 5423–5429 (2003).
Sriram, U. et al. IL-4 suppresses dendritic cell response to type I interferons. J. Immunol. 179, 6446–6455 (2007).
Taylor, B. C. et al. TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis. J. Exp. Med. 206, 655–667 (2009).
Guimond, M. et al. Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nature Immunol. 10, 149–157 (2009). This article describes a new role for IL-7 in regulating CD4+ T cell proliferation. Increased accessibility to IL-7 in lymphopaenic conditions decreases the homeostatic proliferation of CD4+ T cells by decreasing the expression of MHC class II molecules by IL-7Rα-expressing DCs.
Brandt, K., Bulfone-Paus, S., Foster, D. C. & Ruckert, R. Interleukin-21 inhibits dendritic cell activation and maturation. Blood 102, 4090–4098 (2003).
Strengell, M., Lehtonen, A., Matikainen, S. & Julkunen, I. IL-21 enhances SOCS gene expression and inhibits LPS-induced cytokine production in human monocyte-derived dendritic cells. J. Leukoc. Biol. 79, 1279–1285 (2006).
Vignali, D. A., Collison, L. W. & Workman, C. J. How regulatory T cells work. Nature Rev. Immunol. 8, 523–532 (2008).
Szabo, S. J., Sullivan, B. M., Peng, S. L. & Glimcher, L. H. Molecular mechanisms regulating Th1 immune responses. Annu. Rev. Immunol. 21, 713–758 (2003).
Gor, D. O., Rose, N. R. & Greenspan, N. S. TH1–TH2: a procrustean paradigm. Nature Immunol. 4, 503–505 (2003).
Wurster, A. L. et al. Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon γ-producing Th1 cells. J. Exp. Med. 196, 969–977 (2002).
Suto, A., Wurster, A. L., Reiner, S. L. & Grusby, M. J. IL-21 inhibits IFN-γ production in developing Th1 cells through the repression of Eomesodermin expression. J. Immunol. 177, 3721–3727 (2006).
Strengell, M., Sareneva, T., Foster, D., Julkunen, I. & Matikainen, S. IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response. J. Immunol. 169, 3600–3605 (2002).
Pesce, J. et al. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J. Clin. Invest. 116, 2044–2055 (2006).
Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007).
Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007).
Zhou, L. et al. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunol. 8, 967–974 (2007). References 118–120 describe the role of IL-21 in the development of the T H 17 cell lineage and in the inflammatory response.
Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).
Veldhoen, M., Hirota, K., Christensen, J., O'Garra, A. & Stockinger, B. Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J. Exp. Med. 206, 43–49 (2009).
Kryczek, I. et al. Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J. Immunol. 178, 6730–6733 (2007).
Hoyer, K. K., Kuswanto, W. F., Gallo, E. & Abbas, A. K. Distinct roles of helper T-cell subsets in a systemic autoimmune disease. Blood 113, 389–395 (2009).
Amadi-Obi, A. et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nature Med. 13, 711–718 (2007).
Kryczek, I. et al. Cutting edge: opposite effects of IL-1 and IL-2 on the regulation of IL-17+ T cell pool: IL-1 subverts IL-2-mediated suppression. J. Immunol. 179, 1423–1426 (2007).
Ivanov, I. I. et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4, 337–349 (2008).
Coquet, J. M., Chakravarti, S., Smyth, M. J. & Godfrey, D. I. Cutting edge: IL-21 is not essential for Th17 differentiation or experimental autoimmune encephalomyelitis. J. Immunol. 180, 7097–7101 (2008).
Sonderegger, I., Kisielow, J., Meier, R., King, C. & Kopf, M. IL-21 and IL-21R are not required for development of Th17 cells and autoimmunity in vivo. Eur. J. Immunol. 38, 1833–1838 (2008).
Chtanova, T. et al. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J. Immunol. 173, 68–78 (2004).
Vogelzang, A. et al. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29, 127–137 (2008).
Nurieva, R. I. et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29, 138–149 (2008).
Linterman, M. A. et al. Follicular helper T cells are required for systemic autoimmunity. J. Exp. Med. 206, 561–576 (2009).
Coquet, J. M. et al. IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. J. Immunol. 178, 2827–2834 (2007).
Li, Y., Bleakley, M. & Yee, C. IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response. J. Immunol. 175, 2261–2269 (2005).
Hinrichs, C. S. et al. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood 111, 5326–5333 (2008). This study showed the contrasting effects of IL-2 and IL-21 during the priming of CD8+ T cells in an antitumour immune response, indicating that the presence of IL-21 during CD8+ T cell priming results in persistence of the cells in vivo and potent antitumour activity.
Kovacs, J. A. et al. Induction of prolonged survival of CD4+ T lymphocytes by intermittent IL-2 therapy in HIV-infected patients. J. Clin. Invest. 115, 2139–2148 (2005).
Porter, B. O. et al. Inferiority of IL-2 alone versus IL-2 with HAART in maintaining CD4 T cell counts during HAART interruption: a randomized controlled trial. AIDS 23, 203–212 (2009).
Waldmann, T. A. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nature Rev. Immunol. 6, 595–601 (2006).
Beq, S. et al. IL-7 induces immunological improvement in SIV-infected rhesus macaques under antiviral therapy. J. Immunol. 176, 914–922 (2006).
Rosenberg, S. A. et al. IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells. J. Immunother. 29, 313–319 (2006).
Andorsky, D. J. & Timmerman, J. M. Interleukin-21: biology and application to cancer therapy. Expert Opin. Biol. Ther. 8, 1295–1307 (2008).
Al-Shami, A., Spolski, R., Kelly, J., Keane-Myers, A. & Leonard, W. J. A role for TSLP in the development of inflammation in an asthma model. J. Exp. Med. 202, 829–839 (2005).
Zhou, B. et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nature Immunol. 6, 1047–1053 (2005).
Ying, S. et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J. Immunol. 174, 8183–8190 (2005).
Gilmour, K. C. et al. Defective expression of the interleukin-2/interleukin-15 receptor β subunit leads to a natural killer cell-deficient form of severe combined immunodeficiency. Blood 98, 877–879 (2001).
Waldmann, T. A. Anti-Tac (daclizumab, Zenapax) in the treatment of leukemia, autoimmune diseases, and in the prevention of allograft rejection: a 25-year personal odyssey. J. Clin. Immunol. 27, 1–18 (2007).
Mayordomo, J. I. et al. Bone marrow-derived dendritic cells serve as potent adjuvants for peptide-based antitumor vaccines. Stem Cells 15, 94–103 (1997).
Thurner, B. et al. Generation of large numbers of fully mature and stable dendritic cells from leukapheresis products for clinical application. J. Immunol. Methods 223, 1–15 (1999).
Acknowledgements
We thank J.-X. Lin for critical comments. This work was supported by the Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, USA.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
Yrina Rochman, Rosanne Spolski and Warren J. Leonard
New insights into the regulation of T cells by γc family cytokines.
Nature Reviews Immunology 9, 480–490 (2009); doi:10.1038/nri2580
Warren Leonard and Rosanne Spolski are inventors on patents and patent applications related to the γc family cytokines and TSLP.
Related links
Related links
DATABASES
OMIM
FURTHER INFORMATION
Glossary
(XSCID). A recessive, inherited disease in which the gene encoding the common cytokine receptor γ-chain (γc) on the X chromosome is mutated. γc is an essential component of six cytokine receptors and its mutation results in a profound immunodeficiency that accounts for approximately half of all cases of SCID and is characterized by an absence of T cells and natural killer cells. Patients with XSCID have a normal number of B cells but these are non-functional.
Regulatory T cell(TReg cell). A specialized type of CD4+ T cell that can suppress the responses of other T cells. TReg cells provide a crucial mechanism for the maintenance of peripheral T cell tolerance. They are characterized by the expression of the α-chain of the interleukin-2 receptor (IL-2Rα; also known as CD25) and the transcription factor forkhead box P3 (FOXP3).
Plasma cellA non-dividing, terminally differentiated, immunoglobulin-secreting cell of the B cell lineage.
Systemic lupus erythematosus(SLE). An autoimmune disease in which autoantibodies that are specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, especially in the kidneys. Patients with SLE generally have abnormal B and T cell function.
Trans-presentationA process by which the α-chain of the interleukin-15 receptor (IL-15Rα) presents IL-15 in trans to other cells expressing a complex (with an intermediate affinity for IL-15) that contains IL-2Rβ and the common cytokine receptor γ-chain (γc), which then transduce a signal.
Activation-induced cell death(AICD). A process in which activated T cells re-stimulated through their T cell receptor undergo cell death after engagement of cell death receptors, such as CD95 or the tumour necrosis factor receptor, or after exposure to reactive oxygen species.
Type I and type II IFNsInterferons (IFNs) are proteins with potent antiviral activity that are of particular importance during the early response to pathogens. Type I (or viral) IFNs comprise families (α, β and ω) of homologous proteins that interact with a common two-chain receptor (consisting of IFNAR1 and IFNAR2). Type II (or immune) IFN is represented by a single protein (IFNγ) that interacts with a different two-chain receptor (consisting of IFNGR1 and IFNGR2).
DNAse I hypersensitivity sitesSites of nuclease sensitivity when nuclei from cells are exposed to limiting concentrations of DNase I. The digested regions of DNA correspond to sites of open DNA, which might be transcription factor-binding sites or areas of altered nucleosome conformation.
Lamina propriaThe layer of mucosal tissue directly under the mucosal epithelial cell surface of the gastrointestinal tract, in which effector immune cells for mucosal immunity reside.
Experimental autoimmune encephalomyelitis(EAE). An experimental model of multiple sclerosis that is induced by immunization of susceptible animals with myelin-derived antigens, such as myelin basic protein, proteolipid protein or myelin oligodendrocyte glycoprotein.
Germinal centresThese structures, which are found in peripheral lymphoid tissues (for example, the spleen or lymph nodes), are sites of B cell proliferation and selection for clones that produce antigen-specific antibodies of higher affinity.
Sanroque miceAn autoimmune strain of mice that carries a loss-of-function mutation in the gene roquin (also known as Rc3h1). These mice have a T cell-mediated systemic lupus erythematosus-like syndrome and severe autoimmune diabetes when on a susceptible genetic background.
Non-obese diabetic (NOD) miceNOD mice spontaneously develop type 1 diabetes mellitus as a result of autoreactive T cell-mediated destruction of pancreatic β-islet cells.
Rights and permissions
About this article
Cite this article
Rochman, Y., Spolski, R. & Leonard, W. New insights into the regulation of T cells by γc family cytokines. Nat Rev Immunol 9, 480–490 (2009). https://doi.org/10.1038/nri2580
Issue date: July 2009
DOI: https://doi.org/10.1038/nri2580
This article is cited by
-
Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity
EMBO Reports (2024)
-
Pharmacological inhibition of demethylzeylasteral on JAK-STAT signaling ameliorates vitiligo
Journal of Translational Medicine (2023)
-
PD-1 signaling negatively regulates the common cytokine receptor γ chain via MARCH5-mediated ubiquitination and degradation to suppress anti-tumor immunity
Cell Research (2023)
-
Role of thymic stromal lymphopoietin in allergy and beyond
Nature Reviews Immunology (2023)
-
Schlafen 12 restricts HIV-1 latency reversal by a codon-usage dependent post-transcriptional block in CD4+ T cells
Communications Biology (2023)