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T Cells

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Immunology of the Skin

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Abstract

Skin protects the body from continual attack by microbial pathogens and environmental factors. The barrier function of skin is achieved by multiple components including the immune system. Thymus-derived lymphocytes (T cells) and B lymphocytes (B cells) are the major players in the adaptive immune system. T cells expressing T-cell receptor (TCR) α and β chains (αβT cells) control the strength and type of immune responses through multifaceted function. CD4 T cells are multifunctional lymphocytes that are divided into helper T (Th) cell subsets and immune suppressive regulatory T (Treg) cells. Th1 cells produce IFN-γ and protect against intracellular pathogens. Th2 cells produce IL-4 family cytokines and participate in the development of allergic skin diseases, including atopic dermatitis (AD). Th17 cells secrete IL-17, recruit granulocytes to fight against extracellular bacteria and fungi, and play a role in psoriasis. IL-22 produced by Th22 cells activates epithelial cells and mediates acanthosis in psoriasis and AD. On the other hand, Foxp3+ Treg cells mute immune responses partly via TGF-β or IL-10. Tissue resident memory T (Trm) cells—essentially all of which are epidermal CD8 T cells—constitute the first line of defense against repeated infections. CD8 T cells are also engaged in psoriasis, lichen planus, and drug eruptions. Skin harbors innate-like T cells such as natural killer T (NKT) cells as well, whose function is not fully understood. This chapter reviews these αβT cell-subsets.

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References

  1. Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, Jiang S, Kuchroo VK, Mathis D, Roncarolo MG, Rudensky A, Sakaguchi S, Shevach EM, Vignali DA, Ziegler SF (2013) Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol 14(4):307–308. doi:10.1038/ni.2554

    Article  CAS  PubMed  Google Scholar 

  2. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, Sallusto F, Napolitani G (2007) Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 8(6):639–646. doi:10.1038/ni1467

    Article  CAS  PubMed  Google Scholar 

  3. Akimova T, Beier UH, Wang L, Levine MH, Hancock WW (2011) Helios expression is a marker of T cell activation and proliferation. PLoS One 6(8):e24226. doi:10.1371/journal.pone.0024226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Alam MS, Maekawa Y, Kitamura A, Tanigaki K, Yoshimoto T, Kishihara K, Yasutomo K (2010) Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A 107(13):5943–5948. doi:10.1073/pnas.0911755107

    Article  PubMed  PubMed Central  Google Scholar 

  5. Apetoh L, Quintana FJ, Pot C, Joller N, Xiao S, Kumar D, Burns EJ, Sherr DH, Weiner HL, Kuchroo VK (2010) The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat Immunol 11(9):854–861. doi:10.1038/ni.1912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, Reinhart TA, McAllister F, Edeal J, Gaus K, Husain S, Kreindler JL, Dubin PJ, Pilewski JM, Myerburg MM, Mason CA, Iwakura Y, Kolls JK (2008) IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med 14(3):275–281. doi:10.1038/nm1710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Baaten BJ, Tinoco R, Chen AT, Bradley LM (2012) Regulation of antigen-experienced T cells: lessons from the quintessential memory marker CD44. Front Immunol 3:23. doi:10.3389/fimmu.2012.00023

    Article  PubMed  PubMed Central  Google Scholar 

  8. Battaglia M, Stabilini A, Draghici E, Gregori S, Mocchetti C, Bonifacio E, Roncarolo MG (2006) Rapamycin and interleukin-10 treatment induces T regulatory type 1 cells that mediate antigen-specific transplantation tolerance. Diabetes 55(1):40–49

    Article  CAS  PubMed  Google Scholar 

  9. Becher B, Durell BG, Noelle RJ (2002) Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest 110(4):493–497. doi:10.1172/JCI15751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bendelac A, Bonneville M, Kearney JF (2001) Autoreactivity by design: innate B and T lymphocytes. Nat Rev Immunol 1(3):177–186. doi:10.1038/35105052

    Article  CAS  PubMed  Google Scholar 

  11. Berg EL, Yoshino T, Rott LS, Robinson MK, Warnock RA, Kishimoto TK, Picker LJ, Butcher EC (1991) The cutaneous lymphocyte antigen is a skin lymphocyte homing receptor for the vascular lectin endothelial cell-leukocyte adhesion molecule 1. J Exp Med 174(6):1461–1466

    Article  CAS  PubMed  Google Scholar 

  12. Bettelli E, Sullivan B, Szabo SJ, Sobel RA, Glimcher LH, Kuchroo VK (2004) Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J Exp Med 200(1):79–87. doi:10.1084/jem.20031819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Boniface K, Bernard FX, Garcia M, Gurney AL, Lecron JC, Morel F (2005) IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol 174(6):3695–3702

    Article  CAS  PubMed  Google Scholar 

  14. Brembilla NC, Ramirez JM, Chicheportiche R, Sorg O, Saurat JH, Chizzolini C (2011) In vivo dioxin favors interleukin-22 production by human CD4+ T cells in an aryl hydrocarbon receptor (AhR)-dependent manner. PLoS One 6(4):e18741. doi:10.1371/journal.pone.0018741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Burzyn D, Benoist C, Mathis D (2013) Regulatory T cells in nonlymphoid tissues. Nat Immunol 14(10):1007–1013. doi:10.1038/ni.2683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Carbone FR, Mackay LK, Heath WR, Gebhardt T (2013) Distinct resident and recirculating memory T cell subsets in non-lymphoid tissues. Curr Opin Immunol 25(3):329–333. doi:10.1016/j.coi.2013.05.007

    Article  CAS  PubMed  Google Scholar 

  17. Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP, Matsunami N, Ardlie KG, Civello D, Catanese JJ, Leong DU, Panko JM, McAllister LB, Hansen CB, Papenfuss J, Prescott SM, White TJ, Leppert MF, Krueger GG, Begovich AB (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80(2):273–290. doi:10.1086/511051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chang HC, Sehra S, Goswami R, Yao W, Yu Q, Stritesky GL, Jabeen R, McKinley C, Ahyi AN, Han L, Nguyen ET, Robertson MJ, Perumal NB, Tepper RS, Nutt SL, Kaplan MH (2010) The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol 11(6):527–534. doi:10.1038/ni.1867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen Z, Benoist C, Mathis D (2005) How defects in central tolerance impinge on a deficiency in regulatory T cells. Proc Natl Acad Sci U S A 102(41):14735–14740. doi:10.1073/pnas.0507014102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chun T, Byun HJ, Chung HY, Chung YH (2004) The effect of soluble LAG-3 (CD223) treatment in fetal thymic organ culture. Biotechnol Lett 26(17):1371–1377. doi:10.1023/B:BILE.0000045635.63873.96

    Article  CAS  PubMed  Google Scholar 

  21. Clark RA (2010) Skin-resident T cells: the ups and downs of on site immunity. J Invest Dermatol 130(2):362–370. doi:10.1038/jid.2009.247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Clark RA, Chong BF, Mirchandani N, Yamanaka K, Murphy GF, Dowgiert RK, Kupper TS (2006) A novel method for the isolation of skin resident T cells from normal and diseased human skin. J Invest Dermatol 126(5):1059–1070. doi:10.1038/sj.jid.5700199

    Article  CAS  PubMed  Google Scholar 

  23. Clark RA, Huang SJ, Murphy GF, Mollet IG, Hijnen D, Muthukuru M, Schanbacher CF, Edwards V, Miller DM, Kim JE, Lambert J, Kupper TS (2008) Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells. J Exp Med 205(10):2221–2234. doi:10.1084/jem.20071190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Clark RA, Kupper TS (2007) IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin. Blood 109(1):194–202. doi:10.1182/blood-2006-02-002873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Clark RA, Watanabe R, Teague JE, Schlapbach C, Tawa MC, Adams N, Dorosario AA, Chaney KS, Cutler CS, Leboeuf NR, Carter JB, Fisher DC, Kupper TS (2012) Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci Transl Med 4(117):117ra117. doi:10.1126/scitranslmed.3003008

    Article  CAS  Google Scholar 

  26. Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ, Ho AW, Hai JH, Yu JJ, Jung JW, Filler SG, Masso-Welch P, Edgerton M, Gaffen SL (2009) Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med 206(2):299–311. doi:10.1084/jem.20081463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Criado G, Simelyte E, Inglis JJ, Essex D, Williams RO (2009) Indoleamine 2,3 dioxygenase-mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen-induced arthritis. Arthritis Rheum 60(5):1342–1351. doi:10.1002/art.24446

    Article  PubMed  Google Scholar 

  28. Crotty S (2011) Follicular helper CD4 T cells (TFH). Annu Rev Immunol 29:621–663. doi:10.1146/annurev-immunol-031210-101400

    Article  CAS  PubMed  Google Scholar 

  29. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421(6924):744–748. doi:10.1038/nature01355

    Article  CAS  PubMed  Google Scholar 

  30. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM, Pan F (2011) Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146(5):772–784. doi:10.1016/j.cell.2011.07.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, Mitsdoerffer M, Strom TB, Elyaman W, Ho IC, Khoury S, Oukka M, Kuchroo VK (2008) IL-4 inhibits TGF-beta-induced Foxp3+ T cells, and together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol 9(12):1347–1355. doi:10.1038/ni.1677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. de Jong A, Pena-Cruz V, Cheng TY, Clark RA, Van Rhijn I, Moody DB (2010) CD1a-autoreactive T cells are a normal component of the human alphabeta T cell repertoire. Nat Immunol 11(12):1102–1109. doi:10.1038/ni.1956

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, Bettini ML, Vogel P, Finkelstein D, Bonnevier J, Workman CJ, Vignali DA (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501(7466):252–256. doi:10.1038/nature12428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR, Haugen HS, Maurer M, Harder B, Johnston J, Bort S, Mudri S, Kuijper JL, Bukowski T, Shea P, Dong DL, Dasovich M, Grant FJ, Lockwood L, Levin SD, LeCiel C, Waggie K, Day H, Topouzis S, Kramer J, Kuestner R, Chen Z, Foster D, Parrish-Novak J, Gross JA (2004) Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol 5(7):752–760. doi:10.1038/ni1084

    Article  CAS  PubMed  Google Scholar 

  35. Doisne JM, Becourt C, Amniai L, Duarte N, Le Luduec JB, Eberl G, Benlagha K (2009) Skin and peripheral lymph node invariant NKT cells are mainly retinoic acid receptor-related orphan receptor (gamma)t+ and respond preferentially under inflammatory conditions. J Immunol 183(3):2142–2149. doi:10.4049/jimmunol.0901059

    Article  CAS  PubMed  Google Scholar 

  36. Dudda JC, Lembo A, Bachtanian E, Huehn J, Siewert C, Hamann A, Kremmer E, Forster R, Martin SF (2005) Dendritic cells govern induction and reprogramming of polarized tissue-selective homing receptor patterns of T cells: important roles for soluble factors and tissue microenvironments. Eur J Immunol 35(4):1056–1065. doi:10.1002/eji.200425817

    Article  CAS  PubMed  Google Scholar 

  37. Dudda JC, Simon JC, Martin S (2004) Dendritic cell immunization route determines CD8+ T cell trafficking to inflamed skin: role for tissue microenvironment and dendritic cells in establishment of T cell-homing subsets. J Immunol 172(2):857–863

    Article  CAS  PubMed  Google Scholar 

  38. Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F (2009) Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol 10(8):857–863. doi:10.1038/ni.1767

    Article  CAS  PubMed  Google Scholar 

  39. Edele F, Molenaar R, Gutle D, Dudda JC, Jakob T, Homey B, Mebius R, Hornef M, Martin SF (2008) Cutting edge: instructive role of peripheral tissue cells in the imprinting of T cell homing receptor patterns. J Immunol 181(6):3745–3749

    Article  CAS  PubMed  Google Scholar 

  40. Elyaman W, Bradshaw EM, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J, Bettelli E, Oukka M, van Snick J, Renauld JC, Kuchroo VK, Khoury SJ (2009) IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A 106(31):12885–12890. doi:10.1073/pnas.0812530106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Erpenbeck VJ, Hohlfeld JM, Volkmann B, Hagenberg A, Geldmacher H, Braun A, Krug N (2003) Segmental allergen challenge in patients with atopic asthma leads to increased IL-9 expression in bronchoalveolar lavage fluid lymphocytes. J Allergy Clin Immunol 111(6):1319–1327

    Article  CAS  PubMed  Google Scholar 

  42. Eyerich K, Novak N (2013) Immunology of atopic eczema: overcoming the Th1/Th2 paradigm. Allergy 68(8):974–982. doi:10.1111/all.12184

    Article  CAS  PubMed  Google Scholar 

  43. Eyerich S, Eyerich K, Pennino D, Carbone T, Nasorri F, Pallotta S, Cianfarani F, Odorisio T, Traidl-Hoffmann C, Behrendt H, Durham SR, Schmidt-Weber CB, Cavani A (2009) Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest 119(12):3573–3585. doi:10.1172/JCI40202

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Ferber IA, Brocke S, Taylor-Edwards C, Ridgway W, Dinisco C, Steinman L, Dalton D, Fathman CG (1996) Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol 156(1):5–7

    CAS  PubMed  Google Scholar 

  45. Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, Schlawe K, Chang HD, Bopp T, Schmitt E, Klein-Hessling S, Serfling E, Hamann A, Huehn J (2007) Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 5(2):e38. doi:10.1371/journal.pbio.0050038

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4(4):330–336

    Article  CAS  PubMed  Google Scholar 

  47. Fuhlbrigge RC, Kieffer JD, Armerding D, Kupper TS (1997) Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature 389(6654):978–981. doi:10.1038/40166

    Article  CAS  PubMed  Google Scholar 

  48. Fujita H (2013) The role of IL-22 and Th22 cells in human skin diseases. J Dermatol Sci 72(1):3–8. doi:10.1016/j.jdermsci.2013.04.028

    Article  CAS  PubMed  Google Scholar 

  49. Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, Guo B, Herbert DR, Bulfone A, Trentini F, Di Serio C, Bacchetta R, Andreani M, Brockmann L, Gregori S, Flavell RA, Roncarolo MG (2013) Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 19(6):739–746. doi:10.1038/nm.3179

    Article  CAS  PubMed  Google Scholar 

  50. Gebhardt T, Whitney PG, Zaid A, Mackay LK, Brooks AG, Heath WR, Carbone FR, Mueller SN (2011) Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477(7363):216–219. doi:10.1038/nature10339

    Article  CAS  PubMed  Google Scholar 

  51. Gershon RK, Kondo K (1970) Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 18(5):723–737

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O’Shea JJ (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467(7318):967–971. doi:10.1038/nature09447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gor DO, Rose NR, Greenspan NS (2003) TH1-TH2: a procrustean paradigm. Nat Immunol 4(6):503–505. doi:10.1038/ni0603-503

    Article  CAS  PubMed  Google Scholar 

  54. Gottschalk RA, Corse E, Allison JP (2012) Expression of Helios in peripherally induced Foxp3+ regulatory T cells. J Immunol 188(3):976–980. doi:10.4049/jimmunol.1102964

    Article  CAS  PubMed  Google Scholar 

  55. Gran B, Zhang GX, Yu S, Li J, Chen XH, Ventura ES, Kamoun M, Rostami A (2002) IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J Immunol 169(12):7104–7110

    Article  CAS  PubMed  Google Scholar 

  56. Gulen MF, Kang Z, Bulek K, Youzhong W, Kim TW, Chen Y, Altuntas CZ, Sass Bak-Jensen K, McGeachy MJ, Do JS, Xiao H, Delgoffe GM, Min B, Powell JD, Tuohy VK, Cua DJ, Li X (2010) The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation. Immunity 32(1):54–66. doi:10.1016/j.immuni.2009.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Halabi-Tawil M, Ruemmele FM, Fraitag S, Rieux-Laucat F, Neven B, Brousse N, De Prost Y, Fischer A, Goulet O, Bodemer C (2009) Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Br J Dermatol 160(3):645–651. doi:10.1111/j.1365-2133.2008.08835.x

    Article  CAS  PubMed  Google Scholar 

  58. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369(2):134–144. doi:10.1056/NEJMoa1305133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Heath WR, Carbone FR (2013) The skin-resident and migratory immune system in steady state and memory: innate lymphocytes, dendritic cells and T cells. Nat Immunol 14(10):978–985. doi:10.1038/ni.2680

    Article  CAS  PubMed  Google Scholar 

  60. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061

    Article  CAS  PubMed  Google Scholar 

  61. Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, Antoni C, Draelos Z, Gold MH, Psoriasis Study G, Durez P, Tak PP, Gomez-Reino JJ, Rheumatoid Arthritis Study G, Foster CS, Kim RY, Samson CM, Falk NS, Chu DS, Callanan D, Nguyen QD, Uveitis Study G, Rose K, Haider A, Di Padova F (2010) Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 2(52):52ra72. doi:10.1126/scitranslmed.3001107

    Article  PubMed  CAS  Google Scholar 

  62. Huh JR, Leung MW, Huang P, Ryan DA, Krout MR, Malapaka RR, Chow J, Manel N, Ciofani M, Kim SV, Cuesta A, Santori FR, Lafaille JJ, Xu HE, Gin DY, Rastinejad F, Littman DR (2011) Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity. Nature 472(7344):486–490. doi:10.1038/nature09978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ichiyama K, Hashimoto M, Sekiya T, Nakagawa R, Wakabayashi Y, Sugiyama Y, Komai K, Saba I, Moroy T, Yoshimura A (2009) Gfi1 negatively regulates T(h)17 differentiation by inhibiting RORgammat activity. Int Immunol 21(7):881–889. doi:10.1093/intimm/dxp054

    Article  CAS  PubMed  Google Scholar 

  64. Itoh S, Kimura N, Axtell RC, Velotta JB, Gong Y, Wang X, Kajiwara N, Nambu A, Shimura E, Adachi H, Iwakura Y, Saito H, Okumura K, Sudo K, Steinman L, Robbins RC, Nakae S, Fischbein MP (2011) Interleukin-17 accelerates allograft rejection by suppressing regulatory T cell expansion. Circulation 124(11 Suppl):S187–S196. doi:10.1161/CIRCULATIONAHA.110.014852

    Article  CAS  PubMed  Google Scholar 

  65. Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564. doi:10.1146/annurev.immunol.25.022106.141623

    Article  CAS  PubMed  Google Scholar 

  66. Khattri R, Cox T, Yasayko SA, Ramsdell F (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4(4):337–342

    Article  CAS  PubMed  Google Scholar 

  67. Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M, Kisand KV, Ersvaer E, Perheentupa J, Erichsen MM, Bratanic N, Meloni A, Cetani F, Perniola R, Ergun-Longmire B, Maclaren N, Krohn KJ, Pura M, Schalke B, Strobel P, Leite MI, Battelino T, Husebye ES, Peterson P, Willcox N, Meager A (2010) Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med 207(2):299–308. doi:10.1084/jem.20091669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kolls JK, Khader SA (2010) The role of Th17 cytokines in primary mucosal immunity. Cytokine Growth Factor Rev 21(6):443–448. doi:10.1016/j.cytogfr.2010.11.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK (2007) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448(7152):484–487. doi:10.1038/nature05970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kuchroo VK, Anderson AC, Waldner H, Munder M, Bettelli E, Nicholson LB (2002) T cell response in experimental autoimmune encephalomyelitis (EAE): role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire. Annu Rev Immunol 20:101–123. doi:10.1146/annurev.immunol.20.081701.141316

    Article  CAS  PubMed  Google Scholar 

  71. Kurebayashi Y, Nagai S, Ikejiri A, Koyasu S (2013) Recent advances in understanding the molecular mechanisms of the development and function of Th17 cells. Genes Cells: Devoted Mol Cell Mech 18(4):247–265. doi:10.1111/gtc.12039

    Article  CAS  Google Scholar 

  72. Lafaille JJ, Nagashima K, Katsuki M, Tonegawa S (1994) High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell 78(3):399–408

    Article  CAS  PubMed  Google Scholar 

  73. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201(2):233–240. doi:10.1084/jem.20041257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274–293. doi:10.1016/j.cell.2012.03.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lazarevic V, Glimcher LH (2011) T-bet in disease. Nat Immunol 12(7):597–606. doi:10.1038/ni.2059

    Article  CAS  PubMed  Google Scholar 

  76. Le Bras S, Geha RS (2006) IPEX and the role of Foxp3 in the development and function of human Tregs. J Clin Invest 116(6):1473–1475. doi:10.1172/JCI28880

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Lee SW, Choi H, Eun SY, Fukuyama S, Croft M (2011) Nitric oxide modulates TGF-beta-directive signals to suppress Foxp3+ regulatory T cell differentiation and potentiate Th1 development. J Immunol 186(12):6972–6980. doi:10.4049/jimmunol.1100485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, Wu C, Kleinewietfeld M, Kunder S, Hafler DA, Sobel RA, Regev A, Kuchroo VK (2012) Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 13(10):991–999. doi:10.1038/ni.2416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Liu L, Fuhlbrigge RC, Karibian K, Tian T, Kupper TS (2006) Dynamic programming of CD8+ T cell trafficking after live viral immunization. Immunity 25(3):511–520. doi:10.1016/j.immuni.2006.06.019

    Article  CAS  PubMed  Google Scholar 

  80. Luci C, Reynders A, Ivanov II, Cognet C, Chiche L, Chasson L, Hardwigsen J, Anguiano E, Banchereau J, Chaussabel D, Dalod M, Littman DR, Vivier E, Tomasello E (2009) Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin. Nat Immunol 10(1):75–82. doi:10.1038/ni.1681

    Article  CAS  PubMed  Google Scholar 

  81. Mackay LK, Rahimpour A, Ma JZ, Collins N, Stock AT, Hafon ML, Vega-Ramos J, Lauzurica P, Mueller SN, Stefanovic T, Tscharke DC, Heath WR, Inouye M, Carbone FR, Gebhardt T (2013) The developmental pathway for CD103(+)CD8(+) tissue-resident memory T cells of skin. Nat Immunol 14(12):1294–1301. doi:10.1038/ni.2744

    Article  CAS  PubMed  Google Scholar 

  82. Matsumoto M, Atarashi K, Umemoto E, Furukawa Y, Shigeta A, Miyasaka M, Hirata T (2005) CD43 functions as a ligand for E-Selectin on activated T cells. J Immunol 175(12):8042–8050

    Article  CAS  PubMed  Google Scholar 

  83. Miller SA, Weinmann AS (2010) Molecular mechanisms by which T-bet regulates T-helper cell commitment. Immunol Rev 238(1):233–246. doi:10.1111/j.1600-065X.2010.00952.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, Davis J, Hsu A, Asher AI, O’Shea J, Holland SM, Paul WE, Douek DC (2008) Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452(7188):773–776. doi:10.1038/nature06764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Miyara M, Sakaguchi S (2011) Human FoxP3(+)CD4(+) regulatory T cells: their knowns and unknowns. Immunol Cell Biol 89(3):346–351. doi:10.1038/icb.2010.137

    Article  CAS  PubMed  Google Scholar 

  86. Moodycliffe AM, Nghiem D, Clydesdale G, Ullrich SE (2000) Immune suppression and skin cancer development: regulation by NKT cells. Nat Immunol 1(6):521–525. doi:10.1038/82782

    Article  CAS  PubMed  Google Scholar 

  87. Mora JR, Cheng G, Picarella D, Briskin M, Buchanan N, von Andrian UH (2005) Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues. J Exp Med 201(2):303–316. doi:10.1084/jem.20041645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mora JR, von Andrian UH (2006) T-cell homing specificity and plasticity: new concepts and future challenges. Trends Immunol 27(5):235–243. doi:10.1016/j.it.2006.03.007

    Article  CAS  PubMed  Google Scholar 

  89. Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–173. doi:10.1146/annurev.iy.07.040189.001045

    Article  CAS  PubMed  Google Scholar 

  90. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317(5835):256–260. doi:10.1126/science.1145697

    Article  CAS  PubMed  Google Scholar 

  91. Mueller SN, Gebhardt T, Carbone FR, Heath WR (2013) Memory T cell subsets, migration patterns, and tissue residence. Annu Rev Immunol 31:137–161. doi:10.1146/annurev-immunol-032712-095954

    Article  CAS  PubMed  Google Scholar 

  92. Murphy KM, Stockinger B (2010) Effector T cell plasticity: flexibility in the face of changing circumstances. Nat Immunol 11(8):674–680. doi:10.1038/ni.1899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, Gudjonsson JE, Li Y, Tejasvi T, Feng BJ, Ruether A, Schreiber S, Weichenthal M, Gladman D, Rahman P, Schrodi SJ, Prahalad S, Guthery SL, Fischer J, Liao W, Kwok PY, Menter A, Lathrop GM, Wise CA, Begovich AB, Voorhees JJ, Elder JT, Krueger GG, Bowcock AM, Abecasis GR, Collaborative Association Study of P (2009) Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 41(2):199–204. doi:10.1038/ng.311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Noelle RJ, Nowak EC (2010) Cellular sources and immune functions of interleukin-9. Nat Rev Immunol 10(10):683–687. doi:10.1038/nri2848

    Article  CAS  PubMed  Google Scholar 

  95. Nograles KE, Zaba LC, Shemer A, Fuentes-Duculan J, Cardinale I, Kikuchi T, Ramon M, Bergman R, Krueger JG, Guttman-Yassky E (2009) IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin Immunol 123(6):1244–1252. doi:10.1016/j.jaci.2009.03.041, e1242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. O’Shea JJ, Paul WE (2010) Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327(5969):1098–1102. doi:10.1126/science.1178334

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Okamura T, Fujio K, Shibuya M, Sumitomo S, Shoda H, Sakaguchi S, Yamamoto K (2009) CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2. Proc Natl Acad Sci U S A 106(33):13974–13979. doi:10.1073/pnas.0906872106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Okazaki T, Honjo T (2007) PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 19(7):813–824. doi:10.1093/intimm/dxm057

    Article  CAS  PubMed  Google Scholar 

  99. Olivares-Villagomez D, Wang Y, Lafaille JJ (1998) Regulatory CD4(+) T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis. J Exp Med 188(10):1883–1894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Omori M, Ziegler S (2007) Induction of IL-4 expression in CD4(+) T cells by thymic stromal lymphopoietin. J Immunol 178(3):1396–1404

    Article  CAS  PubMed  Google Scholar 

  101. Ouyang W, Beckett O, Ma Q, Li MO (2010) Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 32(5):642–653. doi:10.1016/j.immuni.2010.04.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O’Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 38(4):441–446. doi:10.1038/ng1767

    Article  CAS  PubMed  Google Scholar 

  103. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. doi:10.1038/nrc3239

    Article  CAS  PubMed  Google Scholar 

  104. Pot C, Apetoh L, Kuchroo VK (2011) Type 1 regulatory T cells (Tr1) in autoimmunity. Semin Immunol 23(3):202–208. doi:10.1016/j.smim.2011.07.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Pot C, Jin H, Awasthi A, Liu SM, Lai CY, Madan R, Sharpe AH, Karp CL, Miaw SC, Ho IC, Kuchroo VK (2009) Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol 183(2):797–801. doi:10.4049/jimmunol.0901233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, Migaud M, Israel L, Chrabieh M, Audry M, Gumbleton M, Toulon A, Bodemer C, El-Baghdadi J, Whitters M, Paradis T, Brooks J, Collins M, Wolfman NM, Al-Muhsen S, Galicchio M, Abel L, Picard C, Casanova JL (2011) Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332(6025):65–68. doi:10.1126/science.1200439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C, Cobat A, Ouachee-Chardin M, Toulon A, Bustamante J, Al-Muhsen S, Al-Owain M, Arkwright PD, Costigan C, McConnell V, Cant AJ, Abinun M, Polak M, Bougneres PF, Kumararatne D, Marodi L, Nahum A, Roifman C, Blanche S, Fischer A, Bodemer C, Abel L, Lilic D, Casanova JL (2010) Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med 207(2):291–297. doi:10.1084/jem.20091983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL (2008) Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453(7191):65–71. doi:10.1038/nature06880

    Article  CAS  PubMed  Google Scholar 

  109. Reche PA, Soumelis V, Gorman DM, Clifford T, Liu M, Travis M, Zurawski SM, Johnston J, Liu YJ, Spits H, de Waal MR, Kastelein RA, Bazan JF (2001) Human thymic stromal lymphopoietin preferentially stimulates myeloid cells. J Immunol 167(1):336–343

    Article  CAS  PubMed  Google Scholar 

  110. Ribas A (2012) Tumor immunotherapy directed at PD-1. N Engl J Med 366(26):2517–2519. doi:10.1056/NEJMe1205943

    Article  CAS  PubMed  Google Scholar 

  111. Ribas A, Butterfield LH, Glaspy JA, Economou JS (2003) Current developments in cancer vaccines and cellular immunotherapy. J Clin Onco: Off J Am Soc Clin Oncol 21(12):2415–2432. doi:10.1200/JCO.2003.06.041

    Article  CAS  Google Scholar 

  112. Roncarolo MG, Battaglia M (2007) Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol 7(8):585–598. doi:10.1038/nri2138

    Article  CAS  PubMed  Google Scholar 

  113. Rosenblum MD, Gratz IK, Paw JS, Lee K, Marshak-Rothstein A, Abbas AK (2011) Response to self antigen imprints regulatory memory in tissues. Nature 480(7378):538–542. doi:10.1038/nature10664

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Rudensky AY (2011) Regulatory T cells and Foxp3. Immunol Rev 241(1):260–268. doi:10.1111/j.1600-065X.2011.01018.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Rutz S, Eidenschenk C, Ouyang W (2013) IL-22, not simply a Th17 cytokine. Immunol Rev 252(1):116–132. doi:10.1111/imr.12027

    Article  PubMed  CAS  Google Scholar 

  116. Rutz S, Ouyang W (2011) Regulation of interleukin-10 and interleukin-22 expression in T helper cells. Curr Opin Immunol 23(5):605–612. doi:10.1016/j.coi.2011.07.018

    Article  CAS  PubMed  Google Scholar 

  117. Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T (2001) Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 182:18–32

    Article  CAS  PubMed  Google Scholar 

  118. Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133(5):775–787. doi:10.1016/j.cell.2008.05.009, doi:S0092-8674(08)00624-7 [pii]

    Article  CAS  PubMed  Google Scholar 

  119. Sather BD, Treuting P, Perdue N, Miazgowicz M, Fontenot JD, Rudensky AY, Campbell DJ (2007) Altering the distribution of Foxp3(+) regulatory T cells results in tissue-specific inflammatory disease. J Exp Med 204(6):1335–1347. doi:10.1084/jem.20070081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Sawa S, Cherrier M, Lochner M, Satoh-Takayama N, Fehling HJ, Langa F, Di Santo JP, Eberl G (2010) Lineage relationship analysis of RORgammat+ innate lymphoid cells. Science 330(6004):665–669. doi:10.1126/science.1194597

    Article  CAS  PubMed  Google Scholar 

  121. Sawa S, Lochner M, Satoh-Takayama N, Dulauroy S, Berard M, Kleinschek M, Cua D, Di Santo JP, Eberl G (2011) RORgammat+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat Immunol 12(4):320–326. doi:10.1038/ni.2002

    Article  CAS  PubMed  Google Scholar 

  122. Schenkel JM, Fraser KA, Vezys V, Masopust D (2013) Sensing and alarm function of resident memory CD8(+) T cells. Nat Immunol 14(5):509–513. doi:10.1038/ni.2568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Semenza GL (2007) Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE: Signal Transduct Knowl Environ 2007(407):cm8. doi:10.1126/stke.4072007cm8

    Article  Google Scholar 

  124. Seneschal J, Clark RA, Gehad A, Baecher-Allan CM, Kupper TS (2012) Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 36(5):873–884. doi:10.1016/j.immuni.2012.03.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Shaw MH, Kamada N, Kim YG, Nunez G (2012) Microbiota-induced IL-1beta, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine. J Exp Med 209(2):251–258. doi:10.1084/jem.20111703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208(7):1367–1376. doi:10.1084/jem.20110278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Shin H, Iwasaki A (2012) A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature 491(7424):463–467. doi:10.1038/nature11522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Shin H, Iwasaki A (2013) Tissue-resident memory T cells. Immunol Rev 255(1):165–181. doi:10.1111/imr.12087

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Shiohara T (2009) Fixed drug eruption: pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol 9(4):316–321. doi:10.1097/ACI.0b013e32832cda4c

    Article  PubMed  Google Scholar 

  130. Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, Butcher EC (2007) DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27. Nat Immunol 8(3):285–293. doi:10.1038/ni1433

    Article  CAS  PubMed  Google Scholar 

  131. Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G, Munro CS, Sergeant A, O’Regan G, Bale SJ, Compton JG, DiGiovanna JJ, Presland RB, Fleckman P, McLean WH (2006) Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 38(3):337–342. doi:10.1038/ng1743

    Article  CAS  PubMed  Google Scholar 

  132. Sonnenberg GF, Fouser LA, Artis D (2011) Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol 12(5):383–390. doi:10.1038/ni.2025

    Article  CAS  PubMed  Google Scholar 

  133. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K, Gorman D, Zurawski S, Abrams J, Menon S, McClanahan T, de Waal-Malefyt RR, Bazan F, Kastelein RA, Liu YJ (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3(7):673–680. doi:10.1038/ni805

    CAS  PubMed  Google Scholar 

  134. Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Koyasu S, Locksley RM, McKenzie AN, Mebius RE, Powrie F, Vivier E (2013) Innate lymphoid cells – a proposal for uniform nomenclature. Nat Rev Immunol 13(2):145–149. doi:10.1038/nri3365

    Article  CAS  PubMed  Google Scholar 

  135. Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N, Gerlitzki B, Hoffmann M, Ulges A, Taube C, Dehzad N, Becker M, Stassen M, Steinborn A, Lohoff M, Schild H, Schmitt E, Bopp T (2010) Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33(2):192–202. doi:10.1016/j.immuni.2010.07.014

    Article  CAS  PubMed  Google Scholar 

  136. Streilein JW (1985) Circuits and signals of the skin-associated lymphoid tissues (SALT). J Invest Dermatol 85(1 Suppl):10s–13s

    Article  CAS  PubMed  Google Scholar 

  137. Sundrud MS, Koralov SB, Feuerer M, Calado DP, Kozhaya AE, Rhule-Smith A, Lefebvre RE, Unutmaz D, Mazitschek R, Waldner H, Whitman M, Keller T, Rao A (2009) Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 324(5932):1334–1338. doi:10.1126/science.1172638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sutton C, Brereton C, Keogh B, Mills KH, Lavelle EC (2006) A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med 203(7):1685–1691. doi:10.1084/jem.20060285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Szabo SJ, Sullivan BM, Peng SL, Glimcher LH (2003) Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 21:713–758. doi:10.1146/annurev.immunol.21.120601.140942

    Article  CAS  PubMed  Google Scholar 

  140. Takatori H, Kanno Y, Watford WT, Tato CM, Weiss G, Ivanov II, Littman DR, O’Shea JJ (2009) Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med 206(1):35–41. doi:10.1084/jem.20072713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Takimoto T, Wakabayashi Y, Sekiya T, Inoue N, Morita R, Ichiyama K, Takahashi R, Asakawa M, Muto G, Mori T, Hasegawa E, Saika S, Hara T, Nomura M, Yoshimura A (2010) Smad2 and Smad3 are redundantly essential for the TGF-beta-mediated regulation of regulatory T plasticity and Th1 development. J Immunol 185(2):842–855. doi:10.4049/jimmunol.0904100

    Article  CAS  PubMed  Google Scholar 

  142. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, Shevach EM (2010) Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 184(7):3433–3441. doi:10.4049/jimmunol.0904028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H (2009) Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol 10(8):864–871. doi:10.1038/ni.1770

    Article  CAS  PubMed  Google Scholar 

  144. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453(7191):106–109. doi:10.1038/nature06881

    Article  CAS  PubMed  Google Scholar 

  145. Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, Martin B, Wilhelm C, Stockinger B (2008) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9(12):1341–1346. doi:10.1038/ni.1659

    Article  CAS  PubMed  Google Scholar 

  146. Vignali DA, Collison LW, Workman CJ (2008) How regulatory T cells work. Nat Rev Immunol 8(7):523–532. doi:10.1038/nri2343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Weaver CT, Elson CO, Fouser LA, Kolls JK (2013) The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu Rev Pathol 8:477–512. doi:10.1146/annurev-pathol-011110-130318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25:821–852. doi:10.1146/annurev.immunol.25.022106.141557

    Article  CAS  PubMed  Google Scholar 

  149. Wei G, Abraham BJ, Yagi R, Jothi R, Cui K, Sharma S, Narlikar L, Northrup DL, Tang Q, Paul WE, Zhu J, Zhao K (2011) Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types. Immunity 35(2):299–311. doi:10.1016/j.immuni.2011.08.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Wei L, Vahedi G, Sun HW, Watford WT, Takatori H, Ramos HL, Takahashi H, Liang J, Gutierrez-Cruz G, Zang C, Peng W, O’Shea JJ, Kanno Y (2010) Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity 32(6):840–851. doi:10.1016/j.immuni.2010.06.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Weidinger S, Rodriguez E, Stahl C, Wagenpfeil S, Klopp N, Illig T, Novak N (2007) Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis. J Invest Dermatol 127(3):724–726. doi:10.1038/sj.jid.5700630

    Article  CAS  PubMed  Google Scholar 

  152. Weiner HL (2001) The mucosal milieu creates tolerogenic dendritic cells and T(R)1 and T(H)3 regulatory cells. Nat Immunol 2(8):671–672. doi:10.1038/90604

    Article  CAS  PubMed  Google Scholar 

  153. Wildbaum G, Youssef S, Grabie N, Karin N (1998) Neutralizing antibodies to IFN-gamma-inducing factor prevent experimental autoimmune encephalomyelitis. J Immunol 161(11):6368–6374

    CAS  PubMed  Google Scholar 

  154. Wilhelm C, Hirota K, Stieglitz B, Van Snick J, Tolaini M, Lahl K, Sparwasser T, Helmby H, Stockinger B (2011) An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat Immunol 12(11):1071–1077. doi:10.1038/ni.2133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899):271–275. doi:10.1126/science.1160062

    Article  CAS  PubMed  Google Scholar 

  156. Wolk K, Haugen HS, Xu W, Witte E, Waggie K, Anderson M, Vom Baur E, Witte K, Warszawska K, Philipp S, Johnson-Leger C, Volk HD, Sterry W, Sabat R (2009) IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-gamma are not. J Mol Med (Berl) 87(5):523–536. doi:10.1007/s00109-009-0457-0

    Article  CAS  Google Scholar 

  157. Workman CJ, Vignali DA (2005) Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J Immunol 174(2):688–695

    Article  CAS  PubMed  Google Scholar 

  158. Wu HY, Quintana FJ, da Cunha AP, Dake BT, Koeglsperger T, Starossom SC, Weiner HL (2011) In vivo induction of Tr1 cells via mucosal dendritic cells and AHR signaling. PLoS One 6(8):e23618. doi:10.1371/journal.pone.0023618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C (2008) T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28(1):29–39. doi:10.1016/j.immuni.2007.11.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Zaba LC, Suarez-Farinas M, Fuentes-Duculan J, Nograles KE, Guttman-Yassky E, Cardinale I, Lowes MA, Krueger JG (2009) Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes. J Allergy Clin Immunol 124(5):1022–1030. doi:10.1016/j.jaci.2009.08.046, e1021-1395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Zenewicz LA, Flavell RA (2011) Recent advances in IL-22 biology. Int Immunol 23(3):159–163. doi:10.1093/intimm/dxr001

    Article  CAS  PubMed  Google Scholar 

  162. Zhang F, Meng G, Strober W (2008) Interactions among the transcription factors Runx1, RORgammat and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nat Immunol 9(11):1297–1306. doi:10.1038/ni.1663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Zhang S, Fujita H, Mitsui H, Yanofsky VR, Fuentes-Duculan J, Pettersen JS, Suarez-Farinas M, Gonzalez J, Wang CQ, Krueger JG, Felsen D, Carucci JA (2013) Increased Tc22 and Treg/CD8 ratio contribute to aggressive growth of transplant associated squamous cell carcinoma. PLoS One 8(5):e62154. doi:10.1371/journal.pone.0062154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, Ouyang W (2007) Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445(7128):648–651. doi:10.1038/nature05505

    Article  CAS  PubMed  Google Scholar 

  165. Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY (2007) Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445(7130):936–940. doi:10.1038/nature05563

    Article  CAS  PubMed  Google Scholar 

  166. Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, Abbas AR, Modrusan Z, Ghilardi N, de Sauvage FJ, Ouyang W (2008) Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14(3):282–289. doi:10.1038/nm1720

    Article  CAS  PubMed  Google Scholar 

  167. Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, Ziegler SF, Littman DR (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453(7192):236–240. doi:10.1038/nature06878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Zhu J, Paul WE (2010) Heterogeneity and plasticity of T helper cells. Cell Res 20(1):4–12. doi:10.1038/cr.2009.138

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Zhu J, Peng T, Johnston C, Phasouk K, Kask AS, Klock A, Jin L, Diem K, Koelle DM, Wald A, Robins H, Corey L (2013) Immune surveillance by CD8alphaalpha+ skin-resident T cells in human herpes virus infection. Nature 497(7450):494–497. doi:10.1038/nature12110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare of Japan.

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Authors and Affiliations

  1. Ijinkai Takeda General Hospital, Kyoto, 606-1495, Japan

    Takashi Nomura & Aya Shinohara

  2. Department of Dermatology, Kyoto University, Kyoto, 606-8507, Japan

    Takashi Nomura

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  1. Takashi Nomura
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  2. Aya Shinohara
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Correspondence to Takashi Nomura .

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  1. Department of Dermatology, Kyoto University Grad Sch of Med., Sakyo-ku, Kyoto, Japan

    Kenji Kabashima

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Nomura, T., Shinohara, A. (2016). T Cells. In: Kabashima, K. (eds) Immunology of the Skin. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55855-2_5

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