Essentials of Th17 cell commitment and plasticity

Blood

Volumn 121, Issue 13, 2013, Pages 2402-2414

  Muranski, Pawel ^a   Restifo, Nicholas P ^b  

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

^b NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INTERLEUKIN 17; INTERLEUKIN 17F;

CYTOKINE PRODUCTION; GRAFT VERSUS HOST REACTION; HOST RESISTANCE; HUMAN; INFECTION; NEOPLASM; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHENOTYPIC PLASTICITY; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; TH1 CELL; TH17 CELL; TISSUE INJURY; BIOLOGICAL MODEL; CELL DIFFERENTIATION; CELL POLARITY; IMMUNOLOGICAL MEMORY; IMMUNOLOGY; INNATE IMMUNITY; PHYSIOLOGY;

CELL DIFFERENTIATION; CELL POLARITY; GRAFT VS HOST DISEASE; HUMANS; IMMUNITY, INNATE; IMMUNOLOGIC MEMORY; INFECTION; MODELS, BIOLOGICAL; NEOPLASMS; TH17 CELLS;

MLCS; MLOWN;

EID: 84878392088     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2012-09-378653     Document Type: Review

References (204)

1. Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood. 2008;112(5):1557-1569.
2. Sun JC, Bevan MJ. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science (New York, N.Y.) 2003;300(5617):339-342. (Pubitemid 36433727)
3. Bevan MJ. Helping the CD8(+) T-cell response. Nat Rev Immunol. 2004;4(8):595-602.
4. Swain SL, McKinstry KK, Strutt TM. Expanding roles for CD4+ T cells in immunity to viruses. Nat Rev Immunol. 2012;12(2):136-148.
5. Muranski P, Restifo NP. Adoptive immunotherapy of cancer using CD4(+) T cells. Curr Opin Immunol. 2009;21(2):200-208.
6. Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;136(7):2348-2357. (Pubitemid 16136806)
7. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145-173. (Pubitemid 19138011)
8. Heinzel FP, Sadick MD, Holaday BJ, et al. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989;169(1):59-72. (Pubitemid 19035542)
9. Romagnani S. The Th1/Th2 paradigm. Immunol Today. 1997;18(6):263-266. (Pubitemid 27261442)
10. Parronchi P, Romagnani P, Annunziato F, et al. Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn's disease. Am J Pathol. 1997;150(3):823-832.
11. Leonard JP, Waldburger KE, Goldman SJ. Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med. 1995;181(1):381-386.
12. Afkarian M, Sedy JR, Yang J, et al. T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells. Nat Immunol. 2002;3(6):549-557. (Pubitemid 34662307)
13. Szabo SJ, Kim ST, Costa GL, et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000;100(6):655-669.
14. Oestreich KJ, Weinmann AS. Transcriptional mechanisms that regulate T helper 1 cell differentiation. Curr Opin Immunol. 2012;24(2):191-195.
15. Kaplan MH, Schindler U, Smiley ST, et al. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996;4(3):313-319. (Pubitemid 26132509)
16. Zheng WP, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997;89(4):587-596. (Pubitemid 27511769)
17. Shimoda K, van Deursen J, Sangster MY, et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature. 1996;380(6575):630-633. (Pubitemid 26119016)
18. Robinson DS, Hamid Q, Ying S, et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992;326(5):298-304.
19. Lambrecht BN, De Veerman M, Coyle AJ, et al. Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J Clin Invest. 2000;106(4):551-559. (Pubitemid 30666388)
20. Pearce EJ, Caspar P, Grzych JM, et al. Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J Exp Med. 1991;173(1):159-166.
21. Szabo SJ, Jacobson NG, Dighe AS, et al. Developmental commitment to the Th2 lineage by extinction of IL-12 signaling. Immunity. 1995;2(6):665-675.
22. Ouyang W, Ranganath SH, Weindel K, et al. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity. 1998;9(5):745-755. (Pubitemid 28557602)
23. Usui T, Preiss JC, Kanno Y, et al. T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J Exp Med. 2006;203(3):755-766.
24. Hwang ES, Szabo SJ, Schwartzberg PL, Glimcher LH. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science (New York, N.Y.) 2005;307(5708):430-433. (Pubitemid 40139989)
25. Oestreich KJ, Weinmann AS. T-bet employs diverse regulatory mechanisms to repress transcription. Trends Immunol. 2012;33(2):78-83.
26. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science (New York, N.Y.) 2003; 299(5609):1057-1061. (Pubitemid 36222930)
27. Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744-748. (Pubitemid 36227625)
28. Murphy CA, Langrish CL, Chen Y, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med. 2003;198(12):1951-1957. (Pubitemid 38032126)
29. Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6(11):1123-1132. (Pubitemid 41541790)
30. Park H, Li ZX, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133-1141. (Pubitemid 41541791)
31. Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13(5):715-725.
32. Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201(2):233-240. (Pubitemid 40189432)
33. Hirahara K, Ghoreschi K, Laurence A, et al. Signal transduction pathways and transcriptional regulation in Th17 cell differentiation. Cytokine Growth Factor Rev. 2010;21(6):425-434.
34. Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126(6):1121-1133. (Pubitemid 44380299)
35. Yang XO, Pappu BP, Nurieva R, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008;28(1):29-39.
36. Durant L, Watford WT, Ramos HL, et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity. 2010;32(5):605-615.
37. Schraml BU, Hildner K, Ise W, et al. The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature. 2009;460(7253):405-409.
38. Shi LZ, Wang R, Huang G, et al. HIF1α - dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011;208(7):1367-1376.
39. Brüstle A, Heink S, Huber M, et al. The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol. 2007;8(9):958-966.
40. Zhang F, Meng G, Strober W. Interactions among the transcription factors Runx1, RORgammat and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nat Immunol. 2008;9(11):1297-1306.
41. Ciofani M, Madar A, Galan C, et al. A validated regulatory network for Th17 cell specification. Cell. 2012;151(2):289-303.
42. Yang XP, Ghoreschi K, Steward-Tharp SM, et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol. 2011;12(3):247-254.
43. Laurence A, Tato CM, Davidson TS, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity. 2007;26(3):371-381. (Pubitemid 46413906)
44. Lazarevic V, Chen X, Shim JH, et al. T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nat Immunol. 2011;12(1):96-104.
45. Diveu C, McGeachy MJ, Boniface K, et al. IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells. J Immunol. 2009;182(9):5748-5756.
46. Mathur AN, Chang HC, Zisoulis DG, et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol. 2007;178(8):4901-4907. (Pubitemid 46595272)
47. Yang XO, Panopoulos AD, Nurieva R, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem. 2007;282(13):9358-9363. (Pubitemid 47104613)
48. McGeachy MJ, Bak-Jensen KS, Chen Y, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007;8(12):1390-1397. (Pubitemid 350138974)
49. McGeachy MJ, Chen Y, Tato CM, et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol. 2009;10(3):314-324.
50. Chen Z, Laurence A, O'Shea JJ. Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation. Semin Immunol. 2007;19(6):400-408.
51. Zhou L, Ivanov II, Spolski R, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007;8(9):967-974. (Pubitemid 47300011)
52. Korn T, Bettelli E, Gao W, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 2007;448(7152):484-487. (Pubitemid 47123515)
53. Ghoreschi K, Laurence A, Yang XP, et al. Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling. Nature. 2010;467(7318):967-971.
54. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009:27:519-550.
55. Gulen MF, Bulek K, Xiao H, et al. Inactivation of the enzyme GSK3α by the kinase IKKi promotes AKT-mTOR signaling pathway that mediates interleukin-1-induced Th17 cell maintenance. Immunity. 2012;37(5):800-812.
56. Gulen MF, Kang Z, Bulek K, et al. The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation. Immunity. 2010;32(1):54-66.
57. Chung Y, Chang SH, Martinez GJ, et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity. 2009;30(4):576-587.
58. Chen Q, Yang W, Gupta S, et al. IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor. Immunity. 2008;29(6):899-911.
59. Oida T, Weiner HL. Depletion of TGF-β from fetal bovine serum. J Immunol Methods. 2010;362(1-2):195-198.
60. Gutcher I, Donkor MK, Ma Q, et al. Autocrine transforming growth factor-β1 promotes in vivo Th17 cell differentiation. Immunity. 2011;34(3):396-408.
61. Qin H, Wang L, Feng T, et al. TGF-beta promotes Th17 cell development through inhibition of SOCS3. J Immunol. 2009;183(1):97-105.
62. Veldhoen M, Hocking RJ, Atkins CJ, et al. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24(2):179-189. (Pubitemid 43214587)
63. Zhou L, Lopes JE, Chong MM, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature. 2008;453(7192):236-240. (Pubitemid 351667978)
64. Valmori D, Raffin C, Raimbaud I, et al. Human RORγt+ TH17 cells preferentially differentiate from naive FOXP3+Treg in the presence of lineage-specific polarizing factors. Proc Natl Acad Sci USA. 2010;107(45):19402-19407.
65. Mucida D, Park Y, Kim G, et al. Reciprocal T(H)17 and regulatory T cell differentiation mediated by retinoic acid. Science (New York, N.Y.) 2007;317(5835):256-260. (Pubitemid 47076203)
66. Takahashi H, Kanno T, Nakayamada S, et al. TGF-β and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nat Immunol. 2012;13(6):587-595.
67. Hall JA, Cannons JL, Grainger JR, et al. Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha. Immunity. 2011;34(3):435-447.
68. Veldhoen M, Hirota K, Westendorf AM, et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature. 2008;453(7191):106-109. (Pubitemid 351630329)
69. Stockinger B, Hirota K, Duarte J, et al. External influences on the immune system via activation of the aryl hydrocarbon receptor. Semin Immunol. 2011;23(2):99-105.
70. Wu H-J, Ivanov II, Darce J, et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity. 2010;32(6):815-827.
71. Ivanov II, Atarashi K, Manel N, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009;139(3):485-498.
72. Kriegel MA, Sefik E, Hill JA, et al. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc Natl Acad Sci U.S.A. 2011;108(28):11548-11553.
73. Chen K, McAleer JP, Lin Y, et al. Th17 cells mediate clade-specific, serotype-independent mucosal immunity. Immunity. 2011;35(6):997-1009.
74. Pepper M, Linehan JL, Pagán AJ, et al. Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells. Nat Immunol. 2010;11(1):83-89.
75. Ouyang WJ, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008;28(4):454-467. (Pubitemid 351471762)
76. Khader SA, Gaffen SL, Kolls JK. Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol. 2009;2(5):403-411.
77. Korn T, Bettelli E, Oukka M, et al. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27(1):485-517.
78. Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol. 2009;9(8):556-567.
79. Fossiez F, Djossou O, Chomarat P, et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med. 1996;183(6):2593-2603. (Pubitemid 26193037)
80. Tan W, Huang W, Zhong Q, et al. IL-17 receptor knockout mice have enhanced myelotoxicity and impaired hemopoietic recovery following gamma irradiation. J Immunol. 2006;176(10):6186-6193.
81. Kinugasa T, Sakaguchi T, Gu XB, et al. Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology. 2000;118(6):1001- 1011. (Pubitemid 30346975)
82. Rangel-Moreno J, Carragher DM, de la Luz Garcia-Hernandez M, et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat Immunol. 2011;12(7):639-646.
83. Mangan PR, Harrington LE, O'Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006;441(7090):231-234.
84. Khader SA, Bell GK, Pearl JE, et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol. 2007;8(4):369-377. (Pubitemid 46745412)
85. Lin YY, Ritchea S, Logar A, et al. Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis. Immunity. 2009;31(5):799-810.
86. LeibundGut-Landmann S, Gross O, Robinson MJ, et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol. 2007;8(6):630-638.
87. Wuthrich M, Deepe GS, Klein B. Adaptive immunity to fungi. In: Paul WE, ed. Annual Review of Immunology. Vol 30. Palo Alto, CA: Annual Reviews; 2012:115-148.
88. Liang SC, Tan X-Y, Luxenberg DP, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006;203(10):2271-2279. (Pubitemid 44498362)
89. Aujla SJ, Chan YR, Zheng MQ, et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med. 2008;14(3):275-281. (Pubitemid 351347908)
90. Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu Rev Immunol. 2008;26:57-79. (Pubitemid 351600371)
91. Milner JD, Brenchley JM, Laurence A, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008;452(7188):773-776. (Pubitemid 351521078)
92. Milner JD, Sandler NG, Douek DC. Th17 cells, Job's syndrome and HIV: opportunities for bacterial and fungal infections. Curr Opin HIV AIDS. 2010;5(2):179-183.
93. Siegel AM, Heimall J, Freeman AF, et al. A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. Immunity. 2011;35(5):806-818.
94. Brenchley JM, Paiardini M, Knox KS, et al. Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood. 2008;112(7):2826-2835.
95. Becher B, Durell BG, Noelle RJ. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest. 2002;110(4):493-497. (Pubitemid 34919703)
96. Cargill M, Schrodi SJ, Chang M, et al. A largescale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet. 2007;80(2):273-290. (Pubitemid 46175676)
97. Takaku T, Calado RT, Kajigaya S, et al. Interleukin-23 receptor (IL-23R) gene polymorphisms in acquired aplastic anemia. Ann Hematol. 2009;88(7):653-657.
98. Zwiers A, Kraal L, van de Pouw Kraan TCTM, Wurdinger T, Bouma G, Kraal G. Cutting edge: A variant of the IL-23R gene associated with inflammatory bowel disease induces loss of microRNA regulation and enhanced protein production. J Immunol. 2012;188(4):1573-1577.
99. Spolski R, Wang L, Wan CK, et al. IL-21 promotes the pathologic immune response to pneumovirus infection. J Immunol. 2012;188(4):1924-1932.
100. Huppert J, Closhen D, Croxford A, et al. Cellular mechanisms of IL-17-induced blood-brain barrier disruption. FASEB J. 2010;24(4):1023-1034.
101. Acosta-Rodriguez EV, Rivino L, Geginat J, et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007;8(6):639-646. (Pubitemid 46785128)
102. Nowak EC, Weaver CT, Turner H, et al. IL-9 as a mediator of Th17-driven inflammatory disease. J Exp Med. 2009;206(8):1653-1660.
103. El-Behi M, Ciric B, Dai H, et al. The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol. 2011;12(6):568-575.
104. Codarri L, Gyülvészi G, Tosevski V, et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol. 2011;12(6):560-567.
105. Luger D, Silver PB, Tang J, et al. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J Exp Med. 2008;205(4):799-810. (Pubitemid 351549879)
106. Kroenke MA, Carlson TJ, Andjelkovic AV, et al. IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med. 2008;205(7):1535-1541. (Pubitemid 351962016)
107. Palmer MT, Weaver CT. Autoimmunity: increasing suspects in the CD4+ T cell lineup. Nat Immunol. 2010;11(1):36-40.
108. Yang Y, Weiner J, Liu Y, et al. T-bet is essential for encephalitogenicity of both Th1 and Th17 cells. J Exp Med. 2009;206(7):1549- 1564.
109. Lee Y, Awasthi A, Yosef N, et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol. 2012;13(10):991-999.
110. Segal BM, Constantinescu CS, Raychaudhuri A, et al. Ustekinumab MS Investigators. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 2008;7(9):796-804.
111. Nograles KE, Zaba LC, Guttman-Yassky E, et al. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol. 2008;159(5):1092-1102.
112. Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol. 2009;129(6):1339-1350.
113. Ma HL, Liang S, Li J, et al. IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J Clin Invest. 2008;118(2):597-607. (Pubitemid 351206549)
114. Leonardi CL, Kimball AB, Papp KA, et al. PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371(9625):1665- 1674. (Pubitemid 351671883)
115. Benson JM, Sachs CW, Treacy G, et al. Therapeutic targeting of the IL-12/23 pathways: generation and characterization of ustekinumab. Nat Biotechnol. 2011;29(7):615-624.
116. Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17- receptor antibody for psoriasis. N Engl J Med. 2012;366(13):1181-1189.
117. Ahern PP, Schiering C, Buonocore S, et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity. 2010;33(2):279-288.
118. Monteleone I, Sarra M, Pallone F, et al. Th17-related cytokines in inflammatory bowel diseases: friends or foes? Curr Mol Med. 2012;12(5):592-597.
119. O'Connor W Jr, Kamanaka M, Booth CJ, et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol. 2009;10(6):603-609.
120. Sugimoto K, Ogawa A, Mizoguchi E, et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest. 2008;118(2):534-544. (Pubitemid 351206544)
121. Zenewicz LA, Yancopoulos GD, Valenzuela DM, et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 2008;29(6):947-957.
122. Fantini MC, Rizzo A, Fina D, et al. IL-21 regulates experimental colitis by modulating the balance between Treg and Th17 cells. Eur J Immunol. 2007;37(11):3155-3163. (Pubitemid 350131294)
123. Peluso I, Fantini MC, Fina D, et al. IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J Immunol. 2007;178(2):732-739. (Pubitemid 46095145)
124. Annunziato F, Cosmi L, Santarlasci V, et al. Phenotypic and functional features of human Th17 cells. J Exp Med. 2007;204(8)1849-1861. (Pubitemid 47240944)
125. Cosmi L, De Palma R, Santarlasci V, et al. Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J Exp Med. 2008;205(8):1903-1916.
126. Hueber W, Sands BE, Lewitzky S, et al Secukinumab in Crohn's Disease Study Group. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012;61(12):1693-1700.
127. Sandborn WJ, Feagan BG, Fedorak RN, et al Ustekinumab Crohn's Disease Study Group. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology. 2008;135(4):1130-1141.
128. Buonocore S, Ahern PP, Uhlig HH, et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature. 2010;464(7293):1371-1375.
129. Tesmer LA, Lundy SK, Sarkar S, et al. Th17 cells in human disease. Immunol Rev. 2008;223:87-113. (Pubitemid 351986173)
130. Wilke CM, Bishop K, Fox D, et al. Deciphering the role of Th17 cells in human disease. Trends Immunol. 2011;32(12):603-611.
131. Solt LA, Kumar N, Nuhant P, et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature. 2011;472(7344):491-494.
132. Huh JR, Leung MWL, Huang P, et al. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity. Nature. 2011;472(7344):486-490.
133. Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol. 2012;12(6):443-458.
134. Serody JS, Hill GR. The IL-17 differentiation pathway and its role in transplant outcome. Biol Blood Marrow Transplant. 2012;18(1 Suppl):S56-S61.
135. Carvalho A, Cunha C, Di Ianni M, et al. Prognostic significance of genetic variants in the IL-23/Th17 pathway for the outcome of T cell-depleted allogeneic stem cell transplantation. Bone Marrow Transplant. 2010;45(11):1645-1652.
136. Carlson MJ, West ML, Coghill JM, Panoskaltsis-Mortari A, Blazar BR, Serody JS. In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations. Blood. 2009;113(6):1365-1374.
137. Kappel LW, Goldberg GL, King CG, et al. IL-17 contributes to CD4-mediated graft-versus-host disease. Blood. 2009;113(4):945-952.
138. Iclozan C, Yu Y, Liu C, et al. T helper17 cells are sufficient but not necessary to induce acute graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16(2):170-178.
139. Yu Y, Wang D, Liu C, et al. Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORγt in mice. Blood. 2011;118(18):5011-5020.
140. Laurence A, Amarnath S, Mariotti J, et al. STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. Immunity. 2012;37(2):209-222.
141. Fulton LM, Carlson MJ, Coghill JM, et al. Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORγt. J Immunol. 2012;189(4):1765-1772.
142. Bucher C, Koch L, Vogtenhuber C, et al. IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation. Blood. 2009;114(26):5375-5384.
143. Chen X, Das R, Komorowski R, et al. Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease. Blood. 2009;114(4):891-900.
144. Das R, Komorowski R, Hessner MJ, et al. Blockade of interleukin-23 signaling results in targeted protection of the colon and allows for separation of graft-versus-host and graft-versus-leukemia responses. Blood. 2010;115(25):5249-5258.
145. Nishimori H, Maeda Y, Teshima T, et al. Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17. Blood. 2012;119(1):285-295.
146. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883-899.
147. Li N, Grivennikov SI, Karin M. The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell. 2011;19(4):429-431.
148. Kujawski M, Kortylewski M, Lee H, et al. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest. 2008;118(10):3367- 3377.
149. Kortylewski M, Kujawski M, Wang T, et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med. 2005;11(12):1314-1321. (Pubitemid 41752912)
150. Kryczek I, Wei S, Zou L, et al. Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol. 2007;178(11):6730-6733. (Pubitemid 46847396)
151. Kryczek I, Banerjee M, Cheng P, et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood. 2009;114(6):1141-1149.
152. Muranski P, Restifo NP. Does IL-17 promote tumor growth? Blood. 2009;114(2):231-232.
153. Zou W, Restifo NPT. T(H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol. 2010;10(4):248-256.
154. Tartour E, Fossiez F, Joyeux I, et al. Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res. 1999;59(15):3698-3704. (Pubitemid 29381875)
155. Wang L, Yi T, Kortylewski M, et al. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med. 2009;206(7):1457-1464.
156. He D, Li H, Yusuf N, et al. IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells. J Immunol. 2010;184(5):2281-2288.
157. Benchetrit F, Ciree A, Vives V, et al. Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood. 2002;99(6):2114-2121. (Pubitemid 34525496)
158. Kryczek I, Wei S, Szeliga W, et al. Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood. 2009;114(2):357-359.
159. Chalmin F, Mignot G, Bruchard M, et al. Stat3 and Gfi-1 transcription factors control Th17 cell immunosuppressive activity via the regulation of ectonucleotidase expression. Immunity. 2012;36(3):362-373.
160. Langowski JL, Zhang X, Wu L, et al. IL-23 promotes tumour incidence and growth. Nature. 2006;442(7101):461-465. (Pubitemid 44264796)
161. Stolfi C, Rizzo A, Franzè E, et al. Involvement of interleukin-21 in the regulation of colitis-associated colon cancer. J Exp Med. 2011;208(11):2279-2290.
162. Purwar R, Schlapbach C, Xiao S, et al. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med. 2012;18(8):1248-1253.
163. Overwijk WW, de Visser KE, Tirion FH, et al. Immunological and antitumor effects of IL-23 as a cancer vaccine adjuvant. J Immunol. 2006;176(9):5213-5222.
164. Tong Z, Yang XO, Yan H, et al. A protective role by interleukin-17F in colon tumorigenesis. PLoS ONE. 2012;7(4):e34959.
165. Cho BS, Lim JY, Yahng SA, et al. Circulating IL-17 levels during the peri-transplant period as a predictor for early leukemia relapse after myeloablative allogeneic stem cell transplantation. Ann Hematol. 2012;91(3):439-448.
166. Muranski P, Boni A, Antony PA, et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood. 2008;112(2):362-373.
167. Martin-Orozco N, Muranski P, Chung Y, et al. T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity. 2009;31(5):787-798.
168. Paulos CM, Carpenito C, Plesa G, et al. The inducible costimulator (ICOS) is critical for the development of human T(H)17 cells. Sci Transl Med. 2010;2(55):55ra78.
169. Hinrichs CS, Kaiser A, Paulos CM, et al. Type 17 CD8+ T cells display enhanced anti-tumor immunity [published online ahead of print May 26, 2009]. Blood. 2009;114(3):596-599.
170. Muranski P, Borman ZA, Kerkar SP, et al. Th17 cells are long lived and retain a stem cell-like molecular signature. Immunity. 2011;35(6):972-985.
171. Lee YK, Turner H, Maynard CL, et al. Late developmental plasticity in the
172. Martin-Orozco N, Chung Y, Chang SH, et al. Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol. 2009;39(1):216-224.
173. O'Shea JJ, Lahesmaa R, Vahedi G, et al. Genomic views of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol. 2011;11(4):239-250.
174. Wei G, Wei L, Zhu J, et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity. 2009;30(1):155-167.
175. Hirota K, Duarte JH, Veldhoen M, et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 2011;12(3):255-263.
176. Cosmi L, Cimaz R, Maggi L, et al. Evidence of the transient nature of the Th17 phenotype of CD4+CD161+ T cells in the synovial fluid of patients with juvenile idiopathic arthritis. Arthritis Rheum. 2011;63(8):2504-2515.
177. Hamaï A, Pignon P, Raimbaud I, et al. Human T(H)17 immune cells specific for the tumor antigen MAGE-A3 convert to IFN-γ-secreting cells as they differentiate into effector T cells in vivo. Cancer Res. 2012;72(5):1059-1063.
178. Waddington CH. The Strategy of the Genes. London, United Kingdom: George Allen & Unwin; 1957
179. MacLeod MKL, Clambey ET, Kappler JW, Marrack P. CD4 memory T cells: What are they and what can they do? Seminars in Immunology. 2009;21:53-61.
180. Gattinoni L, Lugli E, Ji Y, et al. A human memory T cell subset with stem cell-like properties. Nat Med. 2011;17(10):1290-1297.
181. Gattinoni L, Zhong XS, Palmer DC, et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med. 2009;15(7):808-813.
182. Gattinoni L, Ji Y, Restifo NP. Wnt/beta-catenin signaling in T-cell immunity and cancer immunotherapy. Clin Cancer Res. 2010;16(19):4695-4701.
183. Yu Q, Sharma A, Ghosh A, et al. T cell factor-1 negatively regulates expression of IL-17 family of cytokines and protects mice from experimental autoimmune encephalomyelitis. J Immunol. 2011;186(7):3946-3952.
184. Yu Q, Sharma A, Oh SY, et al. T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-gamma. Nat Immunol. 2009;10(9):992-999.
185. Gattinoni L, Klebanoff CA, Palmer DC, et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest. 2005;115(6):1616-1626. (Pubitemid 40814670)
186. Klebanoff CA, Gattinoni L, Restifo NP. CD8+ T-cell memory in tumor immunology and immunotherapy. Immunol Rev. 2006;211:214-224. (Pubitemid 43882974)
187. Shi G, Ramaswamy M, Vistica BP, et al. Unlike Th1, Th17 cells mediate sustained autoimmune inflammation and are highly resistant to restimulation-induced cell death. J Immunol. 2009;183(11):7547-7556.
188. Coquet JM, Middendorp S, van der Horst G, et al. The CD27 and CD70 costimulatory pathway inhibits effector function of T helper 17 cells and attenuates associated autoimmunity. Immunity. 2013;38(1):53-65.
189. Pepper M, Pagán AJ, Igyártó BZ, et al. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity. 2011;35(4):583-595.
190. Marshall HD, Chandele A, Jung YW, et al. Differential expression of Ly6C and T-bet distinguish effector and memory Th1 CD4(+) cell properties during viral infection. Immunity. 2011;35(4):633-646.
191. Wirth TC, Xue HH, Rai D, et al. Repetitive antigen stimulation induces stepwise transcriptome diversification but preserves a core signature of memory CD8(+) T cell differentiation. Immunity. 2010;33(1):128-140.
192. Luckey CJ, Weaver CT. Stem-cell-like qualities of immune memory; CD4+ T cells join the party. Cell Stem Cell. 2012;10(2):107-108.
193. Kryczek I, Zhao ED, Liu Y, et al. Human TH17 cells are long-lived effector memory cells. Sci Transl Med. 2011;3(104):ra100.
194. Ma CS, Deenick EK, Batten M, et al. The origins, function, and regulation of T follicular helper cells. J Exp Med. 2012;209(7):1241-1253.
195. Crotty S, Johnston RJ, Schoenberger SP. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol. 2010;11(2):114-120.
196. Liu X, Yan X, Zhong B, et al. Bcl6 expression specifies the T follicular helper cell program in vivo. J Exp Med. 2012;209(10):1841-1852.
197. Crotty S. Follicular helper CD4 T cells (T-FH). In: Paul WE, Littman DR, Yokoyama WM, eds. Annual Review of Immunology. Vol 29. Palo Alto, CA: Annual Reviews; 2011:621-663.
198. Eyerich S, Eyerich K, Pennino D, et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest. 2009;119(12):3573-3585.
199. Trifari S, Spits H. IL-22-producing CD4+ T cells: middle-men between the immune system and its environment. Eur J Immunol. 2010;40(9):2369-2371.
200. Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol. 2009;10:857-863.
201. Kagami S, Rizzo HL, Lee JJ, et al. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol. 2010;130(5):1373-1383.
202. Wilhelm C, Hirota K, Stieglitz B, et al. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat Immunol. 2011;12(11):1071-1077.
203. Wilhelm C, Turner JE, Van Snick J, et al. The many lives of IL-9: a question of survival? Nat Immunol. 2012;13(7):637-641.
204. Zou W, Restifo NP. Nine lives for TH9s? Nat Med. 2012;18(8):1177-1178.