Seminars in Immunopathology

, Volume 35, Issue 6, pp 657–670 | Cite as

Aryl hydrocarbon receptor promotes RORγt+ Group 3 ILCs and controls intestinal immunity and inflammation

  • Ju Qiu
  • Liang ZhouEmail author


Unlike adaptive immune cells that require antigen recognition and functional maturation during infection, innate lymphoid cells (ILCs) usually respond to pathogens promptly and serve as the first line of defense in infectious diseases. RAR-related orphan receptor (RORγt)+ group 3 ILCs are one of the innate cell populations that have recently been intensively studied. During the fetal stage of development, RORγt+ group 3 ILCs (e.g., lymphoid tissue inducer cells) are required for lymphoid organogenesis. In adult mice, RORγt+ group 3 ILCs are abundantly present in the gut to exert immune defensive functions. Under certain circumstances, however, RORγt+ group 3 ILCs can be pathogenic and contribute to intestinal inflammation. Aryl hydrocarbon receptor (Ahr), a ligand-dependent transcriptional factor, is widely expressed by various immune and non-immune cells. In the gut, the ligand for Ahr can be derived/generated from diet, microflora, and/or host cells. Ahr has been shown to regulate different cell populations in the immune system including RORγt+ group 3 ILCs, T helper (Th)17/22 cells, γδT cells, regulatory T cells (Tregs), Tr1 cells, and antigen presenting cells. In this review, we will focus on the development and function of RORγt+ group 3 ILCs, and discuss the role of Ahr in intestinal immunity and inflammation in mice and in humans. A better understanding of the function of Ahr in the gut is important for developing new therapeutic means to target Ahr in future treatment of infectious and autoimmune diseases.


Innate lymphoid cell Aryl hydrocarbon receptor Intestinal immunity and inflammation 



We thank all members of the Zhou Laboratory for their helpful discussion. This work was supported by the National Institutes of Health (AI089954 and AI091962 to LZ) and by a Cancer Research Institute Investigator Award (LZ). Liang Zhou is a Pew Scholar in Biomedical Sciences, supported by the Pew Charitable Trusts.


  1. 1.
    Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133PubMedCrossRefGoogle Scholar
  2. 2.
    Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203:2271–2279PubMedCrossRefGoogle Scholar
  3. 3.
    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 14:282–289PubMedCrossRefGoogle Scholar
  4. 4.
    Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y (2006) IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177:566–573PubMedGoogle Scholar
  5. 5.
    Wu HJ, Ivanov II, Darce J, Hattori K, Shima T, Umesaki Y, Littman DR, Benoist C, Mathis D (2010) Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32:815–827PubMedCrossRefGoogle Scholar
  6. 6.
    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 10:857–863PubMedCrossRefGoogle Scholar
  7. 7.
    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 10:864–871PubMedCrossRefGoogle Scholar
  8. 8.
    Basu R, O'Quinn DB, Silberger DJ, Schoeb TR, Fouser L, Ouyang W, Hatton RD, Weaver CT (2012) Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 37:1061–1075PubMedCrossRefGoogle Scholar
  9. 9.
    Sonnenberg GF, Monticelli LA, Elloso MM, Fouser LA, Artis D (2011) CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34:122–134PubMedCrossRefGoogle Scholar
  10. 10.
    Goodman T, Lefrancois L (1988) Expression of the gamma-delta T-cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature 333:855–858PubMedCrossRefGoogle Scholar
  11. 11.
    Konkel JE, Maruyama T, Carpenter AC, Xiong Y, Zamarron BF, Hall BE, Kulkarni AB, Zhang P, Bosselut R, Chen W (2011) Control of the development of CD8alphaalpha + intestinal intraepithelial lymphocytes by TGF-beta. Nat Immunol 12:312–319PubMedCrossRefGoogle Scholar
  12. 12.
    Carding SR, Egan PJ (2002) Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol 2:336–345PubMedCrossRefGoogle Scholar
  13. 13.
    Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, Wilhelm C, Veldhoen M (2011) Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147:629–640PubMedCrossRefGoogle Scholar
  14. 14.
    Ivanov II, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, Finlay BB, Littman DR (2008) Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4:337–349PubMedCrossRefGoogle Scholar
  15. 15.
    Kobayashi T, Okamoto S, Hisamatsu T, Kamada N, Chinen H, Saito R, Kitazume MT, Nakazawa A, Sugita A, Koganei K, Isobe K, Hibi T (2008) IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease. Gut 57:1682–1689PubMedCrossRefGoogle Scholar
  16. 16.
    Rovedatti L, Kudo T, Biancheri P, Sarra M, Knowles CH, Rampton DS, Corazza GR, Monteleone G, Di Sabatino A, Macdonald TT (2009) Differential regulation of interleukin 17 and interferon gamma production in inflammatory bowel disease. Gut 58:1629–1636PubMedCrossRefGoogle Scholar
  17. 17.
    Kamada N, Hisamatsu T, Okamoto S, Chinen H, Kobayashi T, Sato T, Sakuraba A, Kitazume MT, Sugita A, Koganei K, Akagawa KS, Hibi T (2008) Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Invest 118:2269–2280PubMedGoogle Scholar
  18. 18.
    O'Connor W Jr, Kamanaka M, Booth CJ, Town T, Nakae S, Iwakura Y, Kolls JK, Flavell RA (2009) A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol 10:603–609PubMedCrossRefGoogle Scholar
  19. 19.
    Kamanaka M, Huber S, Zenewicz LA, Gagliani N, Rathinam C, O'Connor W Jr, Wan YY, Nakae S, Iwakura Y, Hao L, Flavell RA (2011) Memory/effector (CD45RB(lo)) CD4 T cells are controlled directly by IL-10 and cause IL-22-dependent intestinal pathology. J Exp Med 208:1027–1040PubMedCrossRefGoogle Scholar
  20. 20.
    Chae WJ, Gibson TF, Zelterman D, Hao L, Henegariu O, Bothwell AL (2010) Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis. Proc Natl Acad Sci U S A 107:5540–5544PubMedCrossRefGoogle Scholar
  21. 21.
    Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B, Jauch D, Taniguchi K, Yu GY, Osterreicher CH, Hung KE, Datz C, Feng Y, Fearon ER, Oukka M, Tessarollo L, Coppola V, Yarovinsky F, Cheroutre H, Eckmann L, Trinchieri G, Karin M (2012) Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491:254–258PubMedGoogle Scholar
  22. 22.
    Nanno M, Shiohara T, Yamamoto H, Kawakami K, Ishikawa H (2007) Gammadelta T cells: firefighters or fire boosters in the front lines of inflammatory responses. Immunol Rev 215:103–113PubMedCrossRefGoogle Scholar
  23. 23.
    Tsuchiya T, Fukuda S, Hamada H, Nakamura A, Kohama Y, Ishikawa H, Tsujikawa K, Yamamoto H (2003) Role of gamma delta T cells in the inflammatory response of experimental colitis mice. J Immunol 171:5507–5513PubMedGoogle Scholar
  24. 24.
    Inagaki-Ohara K, Chinen T, Matsuzaki G, Sasaki A, Sakamoto Y, Hiromatsu K, Nakamura-Uchiyama F, Nawa Y, Yoshimura A (2004) Mucosal T cells bearing TCRgammadelta play a protective role in intestinal inflammation. J Immunol 173:1390–1398PubMedGoogle Scholar
  25. 25.
    Kohyama M, Nanno M, Kawaguchi-Miyashita M, Shimada S, Watanabe M, Hibi T, Kaminogawa S, Ishikawa H (1999) Cytolytic and IFN-gamma-producing activities of gamma delta T cells in the mouse intestinal epithelium are T cell receptor-beta-chain dependent. Proc Natl Acad Sci U S A 96:7451–7455PubMedCrossRefGoogle Scholar
  26. 26.
    Kawaguchi-Miyashita M, Shimada S, Kurosu H, Kato-Nagaoka N, Matsuoka Y, Ohwaki M, Ishikawa H, Nanno M (2001) An accessory role of TCRgammadelta (+) cells in the exacerbation of inflammatory bowel disease in TCRalpha mutant mice. Eur J Immunol 31:980–988PubMedCrossRefGoogle Scholar
  27. 27.
    Spits H, Cupedo T (2012) Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu Rev Immunol 30:647–675PubMedCrossRefGoogle Scholar
  28. 28.
    Spits H, Di Santo JP (2011) The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol 12:21–27PubMedCrossRefGoogle Scholar
  29. 29.
    Tait Wojno ED, Artis D (2012) Innate lymphoid cells: balancing immunity, inflammation, and tissue repair in the intestine. Cell Host Microbe 12:445–457PubMedCrossRefGoogle Scholar
  30. 30.
    Hoyler T, Klose CS, Souabni A, Turqueti-Neves A, Pfeifer D, Rawlins EL, Voehringer D, Busslinger M, Diefenbach A (2012) The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity 37:634–648PubMedCrossRefGoogle Scholar
  31. 31.
    Mjosberg JM, Trifari S, Crellin NK, Peters CP, van Drunen CM, Piet B, Fokkens WJ, Cupedo T, Spits H (2011) Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol 12:1055–1062PubMedCrossRefGoogle Scholar
  32. 32.
    Zhou L (2012) Striking similarity: GATA-3 regulates ILC2 and Th2 cells. Immunity 37:589–591PubMedCrossRefGoogle Scholar
  33. 33.
    Kelly KA, Scollay R (1992) Seeding of neonatal lymph nodes by T cells and identification of a novel population of CD3-CD4+ cells. Eur J Immunol 22:329–334PubMedCrossRefGoogle Scholar
  34. 34.
    Mebius RE, Rennert P, Weissman IL (1997) Developing lymph nodes collect CD4 + CD3- LTbeta + cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity 7:493–504PubMedCrossRefGoogle Scholar
  35. 35.
    Mebius RE, Miyamoto T, Christensen J, Domen J, Cupedo T, Weissman IL, Akashi K (2001) The fetal liver counterpart of adult common lymphoid progenitors gives rise to all lymphoid lineages, CD45 + CD4 + CD3- cells, as well as macrophages. J Immunol 166:6593–6601PubMedGoogle Scholar
  36. 36.
    Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR (2004) An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells. Nat Immunol 5:64–73PubMedCrossRefGoogle Scholar
  37. 37.
    Possot C, Schmutz S, Chea S, Boucontet L, Louise A, Cumano A, Golub R (2011) Notch signaling is necessary for adult, but not fetal, development of RORgammat(+) innate lymphoid cells. Nat Immunol 12:949–958PubMedCrossRefGoogle Scholar
  38. 38.
    Rossi SW, Kim MY, Leibbrandt A, Parnell SM, Jenkinson WE, Glanville SH, McConnell FM, Scott HS, Penninger JM, Jenkinson EJ, Lane PJ, Anderson G (2007) RANK signals from CD4(+)3(−) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J Exp Med 204:1267–1272PubMedCrossRefGoogle Scholar
  39. 39.
    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 206:35–41PubMedCrossRefGoogle Scholar
  40. 40.
    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 330:665–669PubMedCrossRefGoogle Scholar
  41. 41.
    Sanos SL, Bui VL, Mortha A, Oberle K, Heners C, Johner C, Diefenbach A (2009) RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat Immunol 10:83–91PubMedCrossRefGoogle Scholar
  42. 42.
    Cupedo T, Crellin NK, Papazian N, Rombouts EJ, Weijer K, Grogan JL, Fibbe WE, Cornelissen JJ, Spits H (2009) Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC + CD127+ natural killer-like cells. Nat Immunol 10:66–74PubMedCrossRefGoogle Scholar
  43. 43.
    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 10:75–82PubMedCrossRefGoogle Scholar
  44. 44.
    Takayama T, Kamada N, Chinen H, Okamoto S, Kitazume MT, Chang J, Matuzaki Y, Suzuki S, Sugita A, Koganei K, Hisamatsu T, Kanai T, Hibi T (2010) Imbalance of NKp44(+)NKp46(−) and NKp44(−)NKp46(+) natural killer cells in the intestinal mucosa of patients with Crohn's disease. Gastroenterology 139:882–892, 92 e1-3PubMedCrossRefGoogle Scholar
  45. 45.
    Reynders A, Yessaad N, Vu Manh TP, Dalod M, Fenis A, Aubry C, Nikitas G, Escaliere B, Renauld JC, Dussurget O, Cossart P, Lecuit M, Vivier E, Tomasello E (2011) Identity, regulation and in vivo function of gut NKp46 + RORgammat + and NKp46 + RORgammat- lymphoid cells. EMBO J 30:2934–2947PubMedCrossRefGoogle Scholar
  46. 46.
    Vonarbourg C, Mortha A, Bui VL, Hernandez PP, Kiss EA, Hoyler T, Flach M, Bengsch B, Thimme R, Holscher C, Honig M, Pannicke U, Schwarz K, Ware CF, Finke D, Diefenbach A (2010) Regulated expression of nuclear receptor RORgammat confers distinct functional fates to NK cell receptor-expressing RORgammat(+) innate lymphocytes. Immunity 33:736–751PubMedCrossRefGoogle Scholar
  47. 47.
    Satoh-Takayama N, Lesjean-Pottier S, Vieira P, Sawa S, Eberl G, Vosshenrich CA, Di Santo JP (2010) IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors. J Exp Med 207:273–280PubMedCrossRefGoogle Scholar
  48. 48.
    Qiu J, Heller JJ, Guo X, Chen ZM, Fish K, Fu YX, Zhou L (2012) The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36:92–104PubMedCrossRefGoogle Scholar
  49. 49.
    Lee JS, Cella M, McDonald KG, Garlanda C, Kennedy GD, Nukaya M, Mantovani A, Kopan R, Bradfield CA, Newberry RD, Colonna M (2012) AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat Immunol 13:144–151CrossRefGoogle Scholar
  50. 50.
    Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C, Diefenbach A (2011) Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334:1561–1565PubMedCrossRefGoogle Scholar
  51. 51.
    Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, Bucks C, Kane CM, Fallon PG, Pannell R, Jolin HE, McKenzie AN (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464:1367–1370PubMedCrossRefGoogle Scholar
  52. 52.
    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 12:320–326PubMedCrossRefGoogle Scholar
  53. 53.
    Cella M, Fuchs A, Vermi W, Facchetti F, Otero K, Lennerz JK, Doherty JM, Mills JC, Colonna M (2009) A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457:722–725PubMedCrossRefGoogle Scholar
  54. 54.
    Satoh-Takayama N, Vosshenrich CA, Lesjean-Pottier S, Sawa S, Lochner M, Rattis F, Mention JJ, Thiam K, Cerf-Bensussan N, Mandelboim O, Eberl G, Di Santo JP (2008) Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29:958–970PubMedCrossRefGoogle Scholar
  55. 55.
    Van Maele L, Carnoy C, Cayet D, Songhet P, Dumoutier L, Ferrero I, Janot L, Erard F, Bertout J, Leger H, Sebbane F, Benecke A, Renauld JC, Hardt WD, Ryffel B, Sirard JC (2010) TLR5 signaling stimulates the innate production of IL-17 and IL-22 by CD3(neg)CD127+ immune cells in spleen and mucosa. J Immunol 185:1177–1185PubMedCrossRefGoogle Scholar
  56. 56.
    Kinnebrew MA, Buffie CG, Diehl GE, Zenewicz LA, Leiner I, Hohl TM, Flavell RA, Littman DR, Pamer EG (2012) Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36:276–287PubMedCrossRefGoogle Scholar
  57. 57.
    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 209:251–258PubMedCrossRefGoogle Scholar
  58. 58.
    Hughes T, Becknell B, Freud AG, McClory S, Briercheck E, Yu J, Mao C, Giovenzana C, Nuovo G, Wei L, Zhang X, Gavrilin MA, Wewers MD, Caligiuri MA (2010) Interleukin-1beta selectively expands and sustains interleukin-22+ immature human natural killer cells in secondary lymphoid tissue. Immunity 32:803–814PubMedCrossRefGoogle Scholar
  59. 59.
    Coccia M, Harrison OJ, Schiering C, Asquith MJ, Becher B, Powrie F, Maloy KJ (2012) IL-1beta mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4(+) Th17 cells. J Exp Med 209:1595–1609PubMedCrossRefGoogle Scholar
  60. 60.
    Powell N, Walker AW, Stolarczyk E, Canavan JB, Gokmen MR, Marks E, Jackson I, Hashim A, Curtis MA, Jenner RG, Howard JK, Parkhill J, MacDonald TT, Lord GM (2012) The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor + innate lymphoid cells. Immunity 37:674–684PubMedCrossRefGoogle Scholar
  61. 61.
    Manta C, Heupel E, Radulovic K, Rossini V, Garbi N, Riedel CU, Niess JH (2013) CX(3)CR1(+) macrophages support IL-22 production by innate lymphoid cells during infection with Citrobacter rodentium. Mucosal Immunol 6:177–188PubMedCrossRefGoogle Scholar
  62. 62.
    Crellin NK, Trifari S, Kaplan CD, Satoh-Takayama N, Di Santo JP, Spits H (2010) Regulation of cytokine secretion in human CD127(+) LTi-like innate lymphoid cells by Toll-like receptor 2. Immunity 33:752–764PubMedCrossRefGoogle Scholar
  63. 63.
    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 28:29–39PubMedCrossRefGoogle Scholar
  64. 64.
    Wong SH, Walker JA, Jolin HE, Drynan LF, Hams E, Camelo A, Barlow JL, Neill DR, Panova V, Koch U, Radtke F, Hardman CS, Hwang YY, Fallon PG, McKenzie AN (2012) Transcription factor RORalpha is critical for nuocyte development. Nat Immunol 13:229–236PubMedCrossRefGoogle Scholar
  65. 65.
    Halim TY, MacLaren A, Romanish MT, Gold MJ, McNagny KM, Takei F (2012) Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation. Immunity 37:463–474PubMedCrossRefGoogle Scholar
  66. 66.
    He YW, Deftos ML, Ojala EW, Bevan MJ (1998) RORgamma t, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells. Immunity 9:797–806PubMedCrossRefGoogle Scholar
  67. 67.
    Ruan Q, Kameswaran V, Zhang Y, Zheng S, Sun J, Wang J, DeVirgiliis J, Liou HC, Beg AA, Chen YH (2011) The Th17 immune response is controlled by the Rel-RORgamma-RORgamma T transcriptional axis. J Exp Med 208:2321–2333PubMedCrossRefGoogle Scholar
  68. 68.
    Eberl G, Littman DR (2003) The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer's patches. Immunol Rev 195:81–90PubMedCrossRefGoogle Scholar
  69. 69.
    Yokota Y, Mansouri A, Mori S, Sugawara S, Adachi S, Nishikawa S, Gruss P (1999) Development of peripheral lymphoid organs and natural killer cells depends on the helix–loop–helix inhibitor Id2. Nature 397:702–706PubMedCrossRefGoogle Scholar
  70. 70.
    Cherrier M, Sawa S, Eberl G (2012) Notch, Id2, and RORgammat sequentially orchestrate the fetal development of lymphoid tissue inducer cells. J Exp Med 209:729–740PubMedCrossRefGoogle Scholar
  71. 71.
    Beck K, Peak MM, Ota T, Nemazee D, Murre C (2009) Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain loci. J Exp Med 206:2271–2284PubMedCrossRefGoogle Scholar
  72. 72.
    Boos MD, Yokota Y, Eberl G, Kee BL (2007) Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity. J Exp Med 204:1119–1130PubMedCrossRefGoogle Scholar
  73. 73.
    Iavarone A, King ER, Dai XM, Leone G, Stanley ER, Lasorella A (2004) Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages. Nature 432:1040–1045PubMedCrossRefGoogle Scholar
  74. 74.
    Stinson J, Inoue T, Yates P, Clancy A, Norton JD, Sharrocks AD (2003) Regulation of TCF ETS-domain transcription factors by helix–loop–helix motifs. Nucleic Acids Res 31:4717–4728PubMedCrossRefGoogle Scholar
  75. 75.
    Tachibana M, Tenno M, Tezuka C, Sugiyama M, Yoshida H, Taniuchi I (2011) Runx1/Cbfbeta2 complexes are required for lymphoid tissue inducer cell differentiation at two developmental stages. J Immunol 186:1450–1457PubMedCrossRefGoogle Scholar
  76. 76.
    Ichikawa M, Asai T, Saito T, Seo S, Yamazaki I, Yamagata T, Mitani K, Chiba S, Ogawa S, Kurokawa M, Hirai H (2004) AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nat Med 10:299–304PubMedCrossRefGoogle Scholar
  77. 77.
    Setoguchi R, Tachibana M, Naoe Y, Muroi S, Akiyama K, Tezuka C, Okuda T, Taniuchi I (2008) Repression of the transcription factor Th-POK by Runx complexes in cytotoxic T cell development. Science 319:822–825PubMedCrossRefGoogle Scholar
  78. 78.
    Egawa T, Eberl G, Taniuchi I, Benlagha K, Geissmann F, Hennighausen L, Bendelac A, Littman DR (2005) Genetic evidence supporting selection of the Valpha14i NKT cell lineage from double-positive thymocyte precursors. Immunity 22:705–716PubMedCrossRefGoogle Scholar
  79. 79.
    Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR (1996) AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84:321–330PubMedCrossRefGoogle Scholar
  80. 80.
    Aliahmad P, Kaye J (2008) Development of all CD4 T lineages requires nuclear factor TOX. J Exp Med 205:245–256PubMedCrossRefGoogle Scholar
  81. 81.
    Aliahmad P, de la Torre B, Kaye J (2010) Shared dependence on the DNA-binding factor TOX for the development of lymphoid tissue-inducer cell and NK cell lineages. Nat Immunol 11:945–952PubMedCrossRefGoogle Scholar
  82. 82.
    Deftos ML, Bevan MJ (2000) Notch signaling in T cell development. Curr Opin Immunol 12:166–172PubMedCrossRefGoogle Scholar
  83. 83.
    Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137:216–233PubMedCrossRefGoogle Scholar
  84. 84.
    Georgopoulos K, Bigby M, Wang JH, Molnar A, Wu P, Winandy S, Sharpe A (1994) The Ikaros gene is required for the development of all lymphoid lineages. Cell 79:143–156PubMedCrossRefGoogle Scholar
  85. 85.
    Wang JH, Nichogiannopoulou A, Wu L, Sun L, Sharpe AH, Bigby M, Georgopoulos K (1996) Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity 5:537–549PubMedCrossRefGoogle Scholar
  86. 86.
    Chari S, Winandy S (2008) Ikaros regulates Notch target gene expression in developing thymocytes. J Immunol 181:6265–6274PubMedGoogle Scholar
  87. 87.
    Adachi S, Yoshida H, Honda K, Maki K, Saijo K, Ikuta K, Saito T, Nishikawa SI (1998) Essential role of IL-7 receptor alpha in the formation of Peyer's patch anlage. Int Immunol 10:1–6PubMedCrossRefGoogle Scholar
  88. 88.
    Schmutz S, Bosco N, Chappaz S, Boyman O, Acha-Orbea H, Ceredig R, Rolink AG, Finke D (2009) Cutting edge: IL-7 regulates the peripheral pool of adult ROR gamma + lymphoid tissue inducer cells. J Immunol 183:2217–2221PubMedCrossRefGoogle Scholar
  89. 89.
    Meier D, Bornmann C, Chappaz S, Schmutz S, Otten LA, Ceredig R, Acha-Orbea H, Finke D (2007) Ectopic lymphoid-organ development occurs through interleukin 7-mediated enhanced survival of lymphoid-tissue-inducer cells. Immunity 26:643–654PubMedCrossRefGoogle Scholar
  90. 90.
    Fu YX, Chaplin DD (1999) Development and maturation of secondary lymphoid tissues. Annu Rev Immunol 17:399–433PubMedCrossRefGoogle Scholar
  91. 91.
    Spahn TW, Maaser C, Eckmann L, Heidemann J, Lugering A, Newberry R, Domschke W, Herbst H, Kucharzik T (2004) The lymphotoxin-beta receptor is critical for control of murine Citrobacter rodentium-induced colitis. Gastroenterology 127:1463–1473PubMedCrossRefGoogle Scholar
  92. 92.
    Wang Y, Koroleva EP, Kruglov AA, Kuprash DV, Nedospasov SA, Fu YX, Tumanov AV (2010) Lymphotoxin beta receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity 32:403–413PubMedCrossRefGoogle Scholar
  93. 93.
    Tumanov AV, Koroleva EP, Guo X, Wang Y, Kruglov A, Nedospasov S, Fu YX (2011) Lymphotoxin controls the IL-22 protection pathway in Gut innate lymphoid cells during mucosal pathogen challenge. Cell Host Microbe 10:44–53PubMedCrossRefGoogle Scholar
  94. 94.
    Ansel KM, Ngo VN, Hyman PL, Luther SA, Forster R, Sedgwick JD, Browning JL, Lipp M, Cyster JG (2000) A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406:309–314PubMedCrossRefGoogle Scholar
  95. 95.
    Finke D, Acha-Orbea H, Mattis A, Lipp M, Kraehenbuhl J (2002) CD4 + CD3− cells induce Peyer's patch development: role of alpha4beta1 integrin activation by CXCR5. Immunity 17:363–373PubMedCrossRefGoogle Scholar
  96. 96.
    Scandella E, Bolinger B, Lattmann E, Miller S, Favre S, Littman DR, Finke D, Luther SA, Junt T, Ludewig B (2008) Restoration of lymphoid organ integrity through the interaction of lymphoid tissue-inducer cells with stroma of the T cell zone. Nat Immunol 9:667–675PubMedCrossRefGoogle Scholar
  97. 97.
    Bouskra D, Brezillon C, Berard M, Werts C, Varona R, Boneca IG, Eberl G (2008) Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456:507–510PubMedCrossRefGoogle Scholar
  98. 98.
    Lugering A, Ross M, Sieker M, Heidemann J, Williams IR, Domschke W, Kucharzik T (2010) CCR6 identifies lymphoid tissue inducer cells within cryptopatches. Clin Exp Immunol 160:440–449PubMedCrossRefGoogle Scholar
  99. 99.
    Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R (2004) IL-22 increases the innate immunity of tissues. Immunity 21:241–254PubMedCrossRefGoogle Scholar
  100. 100.
    Vaishnava S, Yamamoto M, Severson KM, Ruhn KA, Yu X, Koren O, Ley R, Wakeland EK, Hooper LV (2011) The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 334:255–258PubMedCrossRefGoogle Scholar
  101. 101.
    Stange J, Hepworth MR, Rausch S, Zajic L, Kuhl AA, Uyttenhove C, Renauld JC, Hartmann S, Lucius R (2012) IL-22 mediates host defense against an intestinal intracellular parasite in the absence of IFN-gamma at the cost of Th17-driven immunopathology. J Immunol 188:2410–2418PubMedCrossRefGoogle Scholar
  102. 102.
    Pogonka T, Schelzke K, Stange J, Papadakis K, Steinfelder S, Liesenfeld O, Lucius R (2010) CD8+ cells protect mice against reinfection with the intestinal parasite Eimeria falciformis. Microbes Infect 12:218–226PubMedCrossRefGoogle Scholar
  103. 103.
    De Luca A, Zelante T, D'Angelo C, Zagarella S, Fallarino F, Spreca A, Iannitti RG, Bonifazi P, Renauld JC, Bistoni F, Puccetti P, Romani L (2010) IL-22 defines a novel immune pathway of antifungal resistance. Mucosal Immunol 3:361–373PubMedCrossRefGoogle Scholar
  104. 104.
    Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L, Hansson GC (2008) The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci U S A 105:15064–15069PubMedCrossRefGoogle Scholar
  105. 105.
    Hanash AM, Dudakov JA, Hua G, O'Connor MH, Young LF, Singer NV, West ML, Jenq RR, Holland AM, Kappel LW, Ghosh A, Tsai JJ, Rao UK, Yim NL, Smith OM, Velardi E, Hawryluk EB, Murphy GF, Liu C, Fouser LA, Kolesnick R, Blazar BR, van den Brink MR (2012) Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity 37:339–350PubMedCrossRefGoogle Scholar
  106. 106.
    Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, Flavell RA (2008) Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29:947–957PubMedCrossRefGoogle Scholar
  107. 107.
    Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, Warntjen M, Lehr HA, Hirth S, Weigmann B, Wirtz S, Ouyang W, Neurath MF, Becker C (2009) STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 206:1465–1472PubMedCrossRefGoogle Scholar
  108. 108.
    Lochner M, Ohnmacht C, Presley L, Bruhns P, Si-Tahar M, Sawa S, Eberl G (2011) Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORgamma t and LTi cells. J Exp Med 208:125–134PubMedCrossRefGoogle Scholar
  109. 109.
    Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ, Powrie F (2010) Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464:1371–1375PubMedCrossRefGoogle Scholar
  110. 110.
    Geremia A, Arancibia-Carcamo CV, Fleming MP, Rust N, Singh B, Mortensen NJ, Travis SP, Powrie F (2011) IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med 208:1127–1133PubMedCrossRefGoogle Scholar
  111. 111.
    Garrett WS, Lord GM, Punit S, Lugo-Villarino G, Mazmanian SK, Ito S, Glickman JN, Glimcher LH (2007) Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131:33–45PubMedCrossRefGoogle Scholar
  112. 112.
    Nguyen LP, Bradfield CA (2008) The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol 21:102–116PubMedCrossRefGoogle Scholar
  113. 113.
    Takamura T, Harama D, Matsuoka S, Shimokawa N, Nakamura Y, Okumura K, Ogawa H, Kitamura M, Nakao A (2010) Activation of the aryl hydrocarbon receptor pathway may ameliorate dextran sodium sulfate-induced colitis in mice. Immunol Cell Biol 88:685–689PubMedCrossRefGoogle Scholar
  114. 114.
    Benson JM, Shepherd DM (2011) Aryl hydrocarbon receptor activation by TCDD reduces inflammation associated with Crohn's disease. Toxicol Sci 120:68–78PubMedCrossRefGoogle Scholar
  115. 115.
    Monteleone I, Rizzo A, Sarra M, Sica G, Sileri P, Biancone L, MacDonald TT, Pallone F, Monteleone G (2011) Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141:237–248, 48 e1PubMedCrossRefGoogle Scholar
  116. 116.
    Lehmann GM, Xi X, Kulkarni AA, Olsen KC, Pollock SJ, Baglole CJ, Gupta S, Casey AE, Huxlin KR, Sime PJ, Feldon SE, Phipps RP (2011) The aryl hydrocarbon receptor ligand ITE inhibits TGFbeta1-induced human myofibroblast differentiation. Am J Pathol 178:1556–1567PubMedCrossRefGoogle Scholar
  117. 117.
    Fukunaga BN, Hankinson O (1996) Identification of a novel domain in the aryl hydrocarbon receptor required for DNA binding. J Biol Chem 271:3743–3749PubMedCrossRefGoogle Scholar
  118. 118.
    Gu YZ, Hogenesch JB, Bradfield CA (2000) The PAS superfamily: sensors of environmental and developmental signals. Annu Rev Pharmacol Toxicol 40:519–561PubMedCrossRefGoogle Scholar
  119. 119.
    Schrenk D (1998) Impact of dioxin-type induction of drug-metabolizing enzymes on the metabolism of endo- and xenobiotics. Biochem Pharmacol 55:1155–1162PubMedCrossRefGoogle Scholar
  120. 120.
    Gonzalez FJ, Fernandez-Salguero P (1998) The aryl hydrocarbon receptor: studies using the AHR-null mice. Drug Metab Dispos 26:1194–1198PubMedGoogle Scholar
  121. 121.
    Negishi T, Kato Y, Ooneda O, Mimura J, Takada T, Mochizuki H, Yamamoto M, Fujii-Kuriyama Y, Furusako S (2005) Effects of aryl hydrocarbon receptor signaling on the modulation of TH1/TH2 balance. J Immunol 175:7348–7356PubMedGoogle Scholar
  122. 122.
    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 453:106–109PubMedCrossRefGoogle Scholar
  123. 123.
    >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 453:65–71PubMedCrossRefGoogle Scholar
  124. 124.
    Gandhi R, Kumar D, Burns EJ, Nadeau M, Dake B, Laroni A, Kozoriz D, Weiner HL, Quintana FJ (2010) Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells. Nat Immunol 11:846–853PubMedCrossRefGoogle Scholar
  125. 125.
    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 11:854–861PubMedCrossRefGoogle Scholar
  126. 126.
    Kimura A, Naka T, Nakahama T, Chinen I, Masuda K, Nohara K, Fujii-Kuriyama Y, Kishimoto T (2009) Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses. J Exp Med 206:2027–2035PubMedCrossRefGoogle Scholar
  127. 127.
    Fujii-Kuriyama Y, Kishimoto T (2010) Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci U S A 107:19961–19966Google Scholar
  128. 128.
    Furumatsu K, Nishiumi S, Kawano Y, Ooi M, Yoshie T, Shiomi Y, Kutsumi H, Ashida H, Fujii-Kuriyama Y, Azuma T, Yoshida M (2011) A role of the aryl hydrocarbon receptor in attenuation of colitis. Dig Dis Sci 56:2532–2544PubMedCrossRefGoogle Scholar
  129. 129.
    Singh NP, Singh UP, Singh B, Price RL, Nagarkatti M, Nagarkatti PS (2011) Activation of aryl hydrocarbon receptor (AhR) leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis. PLoS One 6:e23522PubMedCrossRefGoogle Scholar
  130. 130.
    Mimura J, Fujii-Kuriyama Y (2003) Functional role of AhR in the expression of toxic effects by TCDD. Biochim Biophys Acta 1619:263–268PubMedCrossRefGoogle Scholar
  131. 131.
    Veldhoen M, Brucklacher-Waldert V (2012) Dietary influences on intestinal immunity. Nat Rev Immunol 12:696–708PubMedCrossRefGoogle Scholar
  132. 132.
    Ciofani M, Madar A, Galan C, Sellars M, Mace K, Pauli F, Agarwal A, Huang W, Parkurst CN, Muratet M, Newberry KM, Meadows S, Greenfield A, Yang Y, Jain P, Kirigin FK, Birchmeier C, Wagner EF, Murphy KM, Myers RM, Bonneau R, Littman DR (2012) A validated regulatory network for Th17 cell specification. Cell 151:289–303PubMedCrossRefGoogle Scholar
  133. 133.
    Khor B, Gardet A, Xavier RJ (2011) Genetics and pathogenesis of inflammatory bowel disease. Nature 474:307–317PubMedCrossRefGoogle Scholar
  134. 134.
    Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, Diepolder H, Marquardt A, Jagla W, Popp A, Leclair S, Herrmann K, Seiderer J, Ochsenkuhn T, Goke B, Auernhammer CJ, Dambacher J (2006) IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol 290:G827–G838PubMedCrossRefGoogle Scholar
  135. 135.
    Andoh A, Zhang Z, Inatomi O, Fujino S, Deguchi Y, Araki Y, Tsujikawa T, Kitoh K, Kim-Mitsuyama S, Takayanagi A, Shimizu N, Fujiyama Y (2005) Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 129:969–984PubMedCrossRefGoogle Scholar
  136. 136.
    Schmechel S, Konrad A, Diegelmann J, Glas J, Wetzke M, Paschos E, Lohse P, Goke B, Brand S (2008) Linking genetic susceptibility to Crohn's disease with Th17 cell function: IL-22 serum levels are increased in Crohn's disease and correlate with disease activity and IL23R genotype status. Inflamm Bowel Dis 14:204–212PubMedCrossRefGoogle Scholar
  137. 137.
    Wolk K, Witte E, Hoffmann U, Doecke WD, Endesfelder S, Asadullah K, Sterry W, Volk HD, Wittig BM, Sabat R (2007) IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn's disease. J Immunol 178:5973–5981PubMedGoogle Scholar
  138. 138.
    Sonnenberg GF, Monticelli LA, Alenghat T, Fung TC, Hutnick NA, Kunisawa J, Shibata N, Grunberg S, Sinha R, Zahm AM, Tardif MR, Sathaliyawala T, Kubota M, Farber DL, Collman RG, Shaked A, Fouser LA, Weiner DB, Tessier PA, Friedman JR, Kiyono H, Bushman FD, Chang KM, Artis D (2012) Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336:1321–1325PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of Pathology, Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  2. 2.Department of Microbiology-Immunology, Feinberg School of MedicineNorthwestern UniversityChicagoUSA

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