New insights into the regulation of T cells by γc family cytokines

Nature Reviews Immunology

Volumn 9, Issue 7, 2009, Pages 480-490

  Rochman, Yrina ^a   Spolski, Rosanne ^a   Leonard, Warren J ^a  

^a NATIONAL HEART LUNG AND BLOOD INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DACLIZUMAB; INTERLEUKIN 15; INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR GAMMA; INTERLEUKIN 21; INTERLEUKIN 4; INTERLEUKIN 7; INTERLEUKIN 9; PROTEIN ANTIBODY; T LYMPHOCYTE RECEPTOR ALPHA CHAIN; T LYMPHOCYTE RECEPTOR BETA CHAIN; T LYMPHOCYTE RECEPTOR DELTA CHAIN; T LYMPHOCYTE RECEPTOR GAMMA CHAIN; THYMIC STROMAL LYMPHOPOIETIN; THYMIC STROMAL LYMPHOPOIETIN ANTIBODY; UNCLASSIFIED DRUG;

ADAPTIVE IMMUNITY; ALLERGIC DISEASE; ALLERGIC ENCEPHALOMYELITIS; ALLERGIC PNEUMONITIS; ASTHMA; AUTOIMMUNE DISEASE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL LINEAGE; CELL MATURATION; CELL SURVIVAL; CELLULAR IMMUNITY; CLINICAL TRIAL; CYTOKINE PRODUCTION; EFFECTOR CELL; HOMEOSTASIS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNE DEFICIENCY; IMMUNOREGULATION; INNATE IMMUNITY; INSULIN DEPENDENT DIABETES MELLITUS; INTERLEUKIN 2 RECEPTOR BETA DEFICIENCY; INTERLEUKIN 7 RECEPTOR ALPHA DEFICIENCY; JAK3 DEFICIENCY; KIDNEY CARCINOMA; LEUKEMIA; LYMPHOCYTE DIFFERENTIATION; LYMPHOCYTE PROLIFERATION; LYMPHOMA; MELANOMA; MEMORY T LYMPHOCYTE; NEOPLASM; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; REVIEW; SEVERE COMBINED IMMUNODEFICIENCY; SIGNAL TRANSDUCTION; SYSTEMIC LUPUS ERYTHEMATOSUS; TH17 CELL; VIRUS INFECTION; X LINKED SEVERE COMBINED IMMUNODEFICIENCY;

ANIMALS; CELL DIFFERENTIATION; CYTOKINES; HUMANS; INTERLEUKIN RECEPTOR COMMON GAMMA SUBUNIT; SEVERE COMBINED IMMUNODEFICIENCY; SIGNAL TRANSDUCTION; T-LYMPHOCYTE SUBSETS;

EID: 67649876115     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri2580     Document Type: Review

References (149)

1. Leonard, W. J. Cytokines and immunodeficiency diseases. Nature Rev. Immunol. 1, 200-208 (2001).
2. Spolski, R. & Leonard, W. J. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu. Rev. Immunol. 26, 57-79 (2008).
3. Takeshita, T. et al. Cloning of the γ chain of the human IL-2 receptor. Science 257, 379-382 (1992).
4. 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, γc or βc, highlights structural similarities and differences between these families, and discusses their abilities to bind ligands and mediate signalling.
5. 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 γc in the development of T cells and NK cells. The authors correctly speculated that γc has important roles beyond the action of IL-2.
6. 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).
7. Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775-787 (2008).
8. 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).
9. Lenardo, M. J. Interleukin-2 programs mouse αβ T lymphocytes for apoptosis. Nature 353, 858-861 (1991).
10. Holgate, S. T. & Polosa, R. Treatment strategies for allergy and asthma. Nature Rev. Immunol. 8, 218-230 (2008).
11. Macchi, P. et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377, 65-68 (1995).
12. 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).
13. 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).
14. 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).
15. Mazzucchelli, R. & Durum, S. K. Interleukin-7 receptor expression: intelligent design. Nature Rev. Immunol. 7, 144-154 (2007).
16. Surh, C. D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848-862 (2008).
17. 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).
18. 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).
19. Hauber, H. P., Bergeron, C. & Hamid, Q. IL-9 in allergic inflammation. Int. Arch. Allergy Immunol. 134, 79-87 (2004).
20. 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).
21. 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).
22. Datta, S. & Sarvetnick, N. E. IL-21 limits peripheral lymphocyte numbers through T cell homeostatic mechanisms. PLoS ONE 3, e3118 (2008).
23. 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.
24. Leonard, W. J. & Spolski, R. Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nature Rev. Immunol. 5, 688-698 (2005).
25. 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).
26. Pandey, A. et al. Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin. Nature Immunol. 1, 59-64 (2000).
27. 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).
28. 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 γc in lymphocyte homeostasis.
29. 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).
30. 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).
31. 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).
32. 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).
33. Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nature Immunol. 8, 1255-1265 (2007).
34. 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).
35. 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).
36. 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).
37. 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.
38. 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).
39. 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).
40. 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).
41. 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).
42. Al-Shami, A. et al. A role for thymic stromal lymphopoietin in CD4+ T cell development. J. Exp. Med. 200, 159-168 (2004).
43. 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).
44. Rochman, Y. & Leonard, W. J. The role of thymic stromal lymphopoietin in CD8+ T cell homeostasis. J. Immunol. 181, 7699-7705 (2008).
45. 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).
46. 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 antigenspecific CD8 T cells. J. Immunol. 168, 4827-4831 (2002).
47. 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).
48. 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).
49. Purton, J. F. et al. Antiviral CD4+ memory T cells are IL-15 dependent. J. Exp. Med. 204, 951-961 (2007).
50. 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).
51. 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).
52. 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).
53. 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.
54. 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).
55. 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 γc family cytokines as a proliferative agent for CD8+ T cells in vitro and in vivo during an antitumour response.
56. 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).
57. Ozaki, K. et al. A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630-1634 (2002).
58. Allard, E. L. et al. Overexpression of IL-21 promotes massive CD8+ memory T cell accumulation. Eur. J. Immunol. 37, 3069-3077 (2007).
59. 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).
60. Cote-Sierra, J. et al. Interleukin 2 plays a central role in Th2 differentiation. Proc. Natl Acad. Sci. USA 101, 3880-3885 (2004).
61. 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 TH2 cell differentiation. IL-2 activates STAT5, which binds to the Il4 and Il4ra loci and promotes their transcription.
62. 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).
63. Blattman, J. N. et al. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nature Med. 9, 540-547 (2003).
64. 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).
65. 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).
66. 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).
67. 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).
68. Yajima, T. et al. IL-15 regulates CD8+ T cell contraction during primary infection. J. Immunol. 176, 507-515 (2006).
69. Oh, S. et al. IL-15 as a mediator of CD4+ help for CD8+ T cell longevity and avoidance of TRAILmediated apoptosis. Proc. Natl Acad. Sci. USA 105, 5201-5206 (2008).
70. 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).
71. 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).
72. 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).
73. 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).
74. 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).
75. 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.
76. Rochman, Y. & Leonard, W. J. Thymic stromal lymphopoietin: a new cytokine in asthma. Curr. Opin. Pharmacol. 8, 249-254 (2008).
77. 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).
78. Jameson, J. & Havran, W. L. Skin γδ T-cell functions in homeostasis and wound healing. Immunol. Rev. 215, 114-122 (2007).
79. 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).
80. 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).
81. 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).
82. 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).
83. 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 TReg cells. Although IL-2 is not required for TReg cell development, γc-deficient mice are devoid of FOXP3+ TReg cells. These data are consistent with the idea that more than one cytokine contributes to TReg cell development and it is now clear that IL-2, IL-7 and TSLP are three such cytokines (see REFS 94,95).
84. Antony, P. A. et al. Interleukin-2-dependent mechanisms of tolerance and immunity in vivo. J. Immunol. 176, 5255-5266 (2006).
85. 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).
86. Yao, Z. et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109, 4368-4375 (2007).
87. 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).
88. 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).
89. 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).
90. 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).
91. 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).
92. 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).
93. Imada, K. et al. Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity. J. Exp. Med. 188, 2067-2074 (1998).
94. 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 TReg cells, combined deficiency of IL-7 and TSLPR greatly decreases the number of TReg cells, indicating that both IL-7 and TSLP contribute to TReg cell development.
95. 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).
96. 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).
97. 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).
98. Pandiyan, P. & Lenardo, M. J. The control of CD4+CD25+Foxp3+ regulatory T cell survival. Biol. Direct 3, 6 (2008).
99. 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).
100. Zhang, H. et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nature Med. 11, 1238-1243 (2005).
101. Fukao, T. & Koyasu, S. Expression of functional IL-2 receptors on mature splenic dendritic cells. Eur. J. Immunol. 30, 1453-1457 (2000).
102. 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).
103. 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).
104. 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).
105. 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).
106. Sriram, U. et al. IL-4 suppresses dendritic cell response to type I interferons. J. Immunol. 179, 6446-6455 (2007).
107. 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).
108. 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.
109. Brandt, K., Bulfone-Paus, S., Foster, D. C. & Ruckert, R. Interleukin-21 inhibits dendritic cell activation and maturation. Blood 102, 4090-4098 (2003).
110. 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).
111. Vignali, D. A., Collison, L. W. & Workman, C. J. How regulatory T cells work. Nature Rev. Immunol. 8, 523-532 (2008).
112. 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).
113. Gor, D. O., Rose, N. R. & Greenspan, N. S. TH1-TH2: a procrustean paradigm. Nature Immunol. 4, 503-505 (2003).
114. 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).
115. 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).
116. 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).
117. Pesce, J. et al. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J. Clin. Invest. 116, 2044-2055 (2006).
118. Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484-487 (2007).
119. Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480-483 (2007).
120. 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 TH17 cell lineage and in the inflammatory response.
121. Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371-381 (2007).
122. 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).
123. 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).
124. 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).
125. 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).
126. 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).
127. 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).
128. 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).
129. 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).
130. 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).
131. Vogelzang, A. et al. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29, 127-137 (2008).
132. 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).
133. Linterman, M. A. et al. Follicular helper T cells are required for systemic autoimmunity. J. Exp. Med. 206, 561-576 (2009).
134. 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).
135. Li, Y., Bleakley, M. & Yee, C. IL-21 influences the frequency, phenotype, and affinity of the antigenspecific CD8 T cell response. J. Immunol. 175, 2261-2269 (2005).
136. 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.
137. 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).
138. 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).
139. 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).
140. Beq, S. et al. IL-7 induces immunological improvement in SIV-infected rhesus macaques under antiviral therapy. J. Immunol. 176, 914-922 (2006).
141. 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).
142. Andorsky, D. J. & Timmerman, J. M. Interleukin-21: biology and application to cancer therapy. Expert Opin. Biol. Ther. 8, 1295-1307 (2008).
143. 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).
144. Zhou, B. et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nature Immunol. 6, 1047-1053 (2005).
145. 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).
146. 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).
147. 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).
148. 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).
149. 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).