Interleukin-22 signaling in the regulation of intestinal health and disease

Frontiers in Cell and Developmental Biology

Volumn 3, Issue JAN, 2016, Pages

  Parks, Olivia B ^a   Pociask, Derek A ^a   Hodzic, Zerina ^a   Kolls, Jay K ^a   Good, Misty ^a,b  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^b CHILDREN S HOSPITAL OF PITTSBURGH   (United States)

Author keywords

Barrier defense; Epithelial cells; Gastrointestinal tract; Interleukin 22

Indexed keywords

EID: 85053281426     PISSN: None     EISSN: 2296634X     Source Type: Journal    
DOI: 10.3389/fcell.2015.00085     Document Type: Review

References (170)

1. Alam, M. S., Maekawa, Y., Kitamura, A., Tanigaki, K., Yoshimoto, T., Kishihara, K., et al. (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, 5943-5948. doi: 10.1073/pnas.0911755107
2. Andoh, A., Zhang, Z., Inatomi, O., Fujino, S., Deguchi, Y., Araki, Y., et al. (2005). Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 129, 969-984. doi: 10.1053/j.gastro.2005.06.071
3. Backert, I., Koralov, S. B., Wirtz, S., Kitowski, V., Billmeier, U., Martini, E., et al. (2014). STAT3 activation in Th17 and Th22 cells controls IL-22-mediated epithelial host defense during infectious colitis. J. Immunol. 193, 3779-3791. doi: 10.4049/jimmunol.1303076
4. Basu, R., O'Quinn, D. B., Silberger, D. J., Schoeb, T. R., Fouser, L., Ouyang, W., et al. (2012). Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 37, 1061-1075. doi: 10.1016/j.immuni.2012.08.024
5. Bauquet, A. T., Jin, H., Paterson, A. M., Mitsdoerffer, M., Ho, I. C., Sharpe, A. H., et al. (2009). The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat. Immunol. 10, 167-175. doi: 10.1038/ni.1690
6. Bendelac, A., Savage, P. B., and Teyton, L. (2007). The biology of NKT cells. Annu. Rev. Immunol. 25, 297-336. doi: 10.1146/annurev.immunol.25.022106.141711
7. Benlagha, K., Wei, D. G., Veiga, J., Teyton, L., and Bendelac, A. (2005). Characterization of the early stages of thymic NKT cell development. J. Exp. Med. 202, 485-492. doi: 10.1084/jem.20050456
8. Bleicher, L., de Moura, P. R., Watanabe, L., Colau, D., Dumoutier, L., Renauld, J. C., et al. (2008). Crystal structure of the IL-22/IL-22R1 complex and its implications for the IL-22 signaling mechanism. FEBS Lett. 582, 2985-2992. doi: 10.1016/j.febslet.2008.07.046
9. Cash, H. L., Whitham, C. V., Behrendt, C. L., and Hooper, L. V. (2006). Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126-1130. doi: 10.1126/science.1127119
10. Cella, M., Fuchs, A., Vermi, W., Facchetti, F., Otero, K., Lennerz, J. K., et al. (2009). A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722-725. doi: 10.1038/nature07537
11. Cella, M., Miller, H., and Song, C. (2014). Beyond NK cells: the expanding universe of innate lymphoid cells. Front. Immunol. 5:282. doi: 10.3389/fimmu.2014.00282
12. Cella, M., Otero, K., and Colonna, M. (2010). Expansion of human NK-22 cells with IL-7, IL-2, and IL-1beta reveals intrinsic functional plasticity. Proc. Natl. Acad. Sci. U.S.A. 107, 10961-10966. doi: 10.1073/pnas.1005641107
13. Chen, V. L., Surana, N. K., Duan, J., and Kasper, D. L. (2013). Role of murine intestinal interleukin-1 receptor 1-expressing lymphoid tissue inducer-like cells in Salmonella infection. PLoS ONE 8:e65405. doi: 10.1371/journal.pone.0065405
14. Ciccia, F., Guggino, G., Rizzo, A., Ferrante, A., Raimondo, S., Giardina, A., et al. (2012). Potential involvement of IL-22 and IL-22-producing cells in the inflamed salivary glands of patients with Sjogren's syndrome. Ann. Rheum. Dis. 71, 295-301. doi: 10.1136/ard.2011.154013
15. Colonna, M. (2009). Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity 31, 15-23. doi: 10.1016/j.immuni.2009.06.008
16. Couturier, M., Lamarthee, B., Arbez, J., Renauld, J. C., Bossard, C., Malard, F., et al. (2013). IL-22 deficiency in donor T cells attenuates murine acute graft-versus-host disease mortality while sparing the graft-versus-leukemia effect. Leukemia 27, 1527-1537. doi: 10.1038/leu.2013.39
17. Crellin, N. K., Trifari, S., Kaplan, C. D., Cupedo, T., and Spits, H. (2010). Human NKp44+IL-22+ cells and LTi-like cells constitute a stable RORC+ lineage distinct from conventional natural killer cells. J. Exp. Med. 207, 281-290. doi: 10.1084/jem.20091509
18. Cupedo, T., Crellin, N. K., Papazian, N., Rombouts, E. J., Weijer, K., Grogan, J. L., et al. (2009). Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat. Immunol. 10, 66-74. doi: 10.1038/ni.1668
19. Cupedo, T., Jansen, W., Kraal, G., and Mebius, R. E. (2004). Induction of secondary and tertiary lymphoid structures in the skin. Immunity 21, 655-667. doi: 10.1016/j.immuni.2004.09.006
20. Delsing, C. E., Bleeker-Rovers, C. P., van de Veerdonk, F. L., Tol, J., van der Meer, J. W., Kullberg, B. J., et al. (2012). Association of esophageal candidiasis and squamous cell carcinoma. Med. Mycol. Case Rep. 1, 5-8. doi: 10.1016/j.mmcr.2012.02.003
21. Denison, M. S., and Nagy, S. R. (2003). Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. Toxicol. 43, 309-334. doi: 10.1146/annurev.pharmtox.43.100901.135828
22. Diefenbach, A. (2012). Interleukin-22, the guardian of the intestinal stem cell niche? Immunity 37, 196-198. doi: 10.1016/j.immuni.2012.08.007
23. Doisne, J. M., Soulard, V., Becourt, C., Amniai, L., Henrot, P., Havenar-Daughton, C., et al. (2011). Cutting edge: crucial role of IL-1 and IL-23 in the innate IL-17 response of peripheral lymph node NK1.1-invariant NKT cells to bacteria. J. Immunol. 186, 662-666. doi: 10.4049/jimmunol.1002725
24. Dudakov, J. A., Hanash, A. M., and van den Brink, M. R. (2015). Interleukin-22: immunobiology and pathology. Annu. Rev. Immunol. 33, 747-785. doi: 10.1146/annurev-immunol-032414-112123
25. Duhen, T., Geiger, R., Jarrossay, D., Lanzavecchia, A., and Sallusto, F. (2009). Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat. Immunol. 10, 857-863. doi: 10.1038/ni.1767
26. Dumoutier, L., Lejeune, D., Colau, D., and Renauld, J. C. (2001). Cloning and characterization of IL-22 binding protein, a natural antagonist of IL-10-related T cell-derived inducible factor/IL-22. J. Immunol. 166, 7090-7095. doi: 10.4049/jimmunol.166.12.7090
27. Dumoutier, L., Louahed, J., and Renauld, J. C. (2000a). Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J. Immunol. 164, 1814-1819. doi: 10.4049/jimmunol.164.4.1814
28. Dumoutier, L., Van Roost, E., Ameye, G., Michaux, L., and Renauld, J. C. (2000b). IL-TIF/IL-22: genomic organization and mapping of the human and mouse genes. Genes Immun. 1, 488-494. doi: 10.1038/sj.gene.6363716
29. Dumoutier, L., Van Roost, E., Colau, D., and Renauld, J. C. (2000c). Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor. Proc. Natl. Acad. Sci. U.S.A. 97, 10144-10149. doi: 10.1073/pnas.170291697
30. Eberl, G., Colonna, M., Di Santo, J. P., and McKenzie, A. N. (2015). Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology. Science 348, aaa6566. doi: 10.1126/science.aaa6566
31. Eberl, G., and Littman, D. R. (2003). The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer's patches. Immunol. Rev. 195, 81-90. doi: 10.1034/j.1600-065X.2003.00074.x
32. Edelblum, K. L., Singh, G., Odenwald, M. A., Lingaraju, A., El Bissati, K., McLeod, R., et al. (2015). gammadelta intraepithelial lymphocyte migration limits transepithelial pathogen invasion and systemic disease in mice. Gastroenterology 148, 1417-1426. doi: 10.1053/j.gastro.2015.02.053
33. Eriguchi, Y., Takashima, S., Oka, H., Shimoji, S., Nakamura, K., Uryu, H., et al. (2012). Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of alpha-defensins. Blood 120, 223-231. doi: 10.1182/blood-2011-12-401166
34. Esser, C., Rannug, A., and Stockinger, B. (2009). The aryl hydrocarbon receptor in immunity. Trends Immunol. 30, 447-454. doi: 10.1016/j.it.2009.06.005
35. Fallon, P. G., Ballantyne, S. J., Mangan, N. E., Barlow, J. L., Dasvarma, A., Hewett, D. R., et al. (2006). Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J. Exp. Med. 203, 1105-1116. doi: 10.1084/jem.20051615
36. Finke, D. (2005). Fate and function of lymphoid tissue inducer cells. Curr. Opin. Immunol. 17, 144-150. doi: 10.1016/j.coi.2005.01.006
37. Fuell, C., Kober, O. I., Hautefort, I., and Juge, N. (2015). Mice deficient in intestinal gammadelta intraepithelial lymphocytes display an altered intestinal O-glycan profile compared with wild-type littermates. Glycobiology 25, 42-54. doi: 10.1093/glycob/cwu088
38. Gallo, R. L., and Hooper, L. V. (2012). Epithelial antimicrobial defence of the skin and intestine. Nat. Rev. Immunol. 12, 503-516. doi: 10.1038/nri3228
39. Generon Corporation (Shanghai) Memorial Sloan Kettering Cancer (2016). Study of IL-22 IgG2-Fc (F-652) for Subjects With Grade II-IV Lower GI aGVHD. New York, NY
40. Gladiator, A., Wangler, N., Trautwein-Weidner, K., and Leibundgut-Landmann, S. (2013). Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J. Immunol. 190, 521-525. doi: 10.4049/jimmunol.1202924
41. Godfrey, D. I., Stankovic, S., and Baxter, A. G. (2010). Raising the NKT cell family. Nat. Immunol. 11, 197-206. doi: 10.1038/ni.1841
42. Goto, Y., Obata, T., Kunisawa, J., Sato, S., Ivanov, I. I., Lamichhane, A., et al. (2014). Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 345, 1254009. doi: 10.1126/science.1254009
43. Hanash, A. M., Dudakov, J. A., Hua, G., O'Connor, M. H., Young, L. F., Singer, N. V., et al. (2012). Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity 37, 339-350. doi: 10.1016/j.immuni.2012.05.028
44. Hasegawa, M., Yada, S., Liu, M. Z., Kamada, N., Munoz-Planillo, R., Do, N., et al. (2014). Interleukin-22 regulates the complement system to promote resistance against pathobionts after pathogen-induced intestinal damage. Immunity 41, 620-632. doi: 10.1016/j.immuni.2014.09.010
45. Hepworth, M. R., Monticelli, L. A., Fung, T. C., Ziegler, C. G., Grunberg, S., Sinha, R., et al. (2013). Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature 498, 113-117. doi: 10.1038/nature12240
46. Hernández, P. P., Mahlakõiv, T., Yang, I., Schwierzeck, V., Nguyen, N., Guendel, F., et al. (2015). Interferon-lambda and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection. Nat. Immunol. 16, 698-707. doi: 10.1038/ni.3180
47. Hoyler, T., Klose, C. S., Souabni, A., Turqueti-Neves, A., Pfeifer, D., Rawlins, E. L., et al. (2012). The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity 37, 634-648. doi: 10.1016/j.immuni.2012.06.020
48. Huber, S., Gagliani, N., Zenewicz, L. A., Huber, F. J., Bosurgi, L., Hu, B., et al. (2012). IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259-263. doi: 10.1038/nature11535
49. Hughes, T., Becknell, B., Freud, A. G., McClory, S., Briercheck, E., Yu, J., et al. (2010). Interleukin-1beta selectively expands and sustains interleukin-22+ immature human natural killer cells in secondary lymphoid tissue. Immunity 32, 803-814. doi: 10.1016/j.immuni.2010.06.007
50. Hughes, T., Becknell, B., McClory, S., Briercheck, E., Freud, A. G., Zhang, X., et al. (2009). Stage 3 immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the TH 17 cytokine interleukin-22. Blood 113, 4008-4010. doi: 10.1182/blood-2008-12-192443
51. Ikeuchi, H., Kuroiwa, T., Hiramatsu, N., Kaneko, Y., Hiromura, K., Ueki, K., et al. (2005). Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum. 52, 1037-1046. doi: 10.1002/art.20965
52. Ivanov, I. I., Atarashi, K., Manel, N., Brodie, E. L., Shima, T., Karaoz, U., et al. (2009). Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485-498. doi: 10.1016/j.cell.2009.09.033
53. Jones, B. C., Logsdon, N. J., and Walter, M. R. (2008). Structure of IL-22 bound to its high-affinity IL-22R1 chain. Structure 16, 1333-1344. doi: 10.1016/j.str.2008.06.005
54. Kärner, J., Meager, A., Laan, M., Maslovskaja, J., Pihlap, M., Remm, A., et al. (2013). Anti-cytokine autoantibodies suggest pathogenetic links with autoimmune regulator deficiency in humans and mice. Clin. Exp. Immunol. 171, 263-272. doi: 10.1111/cei.12024
55. Kastelein, R. A., Hunter, C. A., and Cua, D. J. (2007). Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25, 221-242. doi: 10.1146/annurev.immunol.22.012703.104758
56. Kato-Kogoe, N., Nishioka, T., Kawabe, M., Kataoka, F., Yamanegi, K., Yamada, N., et al. (2012). The promotional effect of IL-22 on mineralization activity of periodontal ligament cells. Cytokine 59, 41-48. doi: 10.1016/j.cyto.2012.03.024
57. Kim, C. J., Nazli, A., Rojas, O. L., Chege, D., Alidina, Z., Huibner, S., et al. (2012). A role for mucosal IL-22 production and Th22 cells in HIV-associated mucosal immunopathogenesis. Mucosal Immunol. 5, 670-680. doi: 10.1038/mi.2012.72
58. Klose, C. S., Flach, M., Möhle, L., Rogell, L., Hoyler, T., Ebert, K., et al. (2014). Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157, 340-356. doi: 10.1016/j.cell.2014.03.030
59. Kolls, J. K., McCray, P. B. Jr., and Chan, Y. R. (2008). Cytokine-mediated regulation of antimicrobial proteins. Nat. Rev. Immunol. 8, 829-835. doi: 10.1038/nri2433
60. Korn, L. L., Thomas, H. L., Hubbeling, H. G., Spencer, S. P., Sinha, R., Simkins, H. M., et al. (2014). Conventional CD4+ T cells regulate IL-22-producing intestinal innate lymphoid cells. Mucosal Immunol. 7, 1045-1057. doi: 10.1038/mi.2013.121
61. Kotenko, S. V., Izotova, L. S., Mirochnitchenko, O. V., Esterova, E., Dickensheets, H., Donnelly, R. P., et al. (2001). Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity. J. Immunol. 166, 7096-7103. doi: 10.4049/jimmunol.166.12.7096
62. Kotenko, S. V., Krause, C. D., Izotova, L. S., Pollack, B. P., Wu, W., and Pestka, S. (1997). Identification and functional characterization of a second chain of the interleukin-10 receptor complex. EMBO J. 16, 5894-5903. doi: 10.1093/emboj/16.19.5894
63. Laakso, S. M., Kekäläinen, E., Heikkilä, N., Mannerström, H., Kisand, K., Peterson, P., et al. (2014). In vivo analysis of helper T cell responses in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy provides evidence in support of an IL-22 defect. Autoimmunity 47, 556-562. doi: 10.3109/08916934.2014.929666
64. Langrish, C. L., McKenzie, B. S., Wilson, N. J., de Waal Malefyt, R., Kastelein, R. A., and Cua, D. J. (2004). IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol. Rev. 202, 96-105. doi: 10.1111/j.0105-2896.2004.00214.x
65. Lee, J. S., Cella, M., McDonald, K. G., Garlanda, C., Kennedy, G. D., Nukaya, M., et al. (2012). AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat. Immunol. 13, 144-151. doi: 10.1038/ni.2187
66. Lee, Y., Kumagai, Y., Jang, M. S., Kim, J. H., Yang, B. G., Lee, E. J., et al. (2013). Intestinal Lin-c-Kit+ NKp46-CD4-population strongly produces IL-22 upon IL-1beta stimulation. J. Immunol. 190, 5296-5305. doi: 10.4049/jimmunol.1201452
67. Lee, Y. S., Yang, H., Yang, J. Y., Kim, Y., Lee, S. H., Kim, J. H., et al. (2015). Interleukin-1 (IL-1) signaling in intestinal stromal cells controls KC/ CXCL1 secretion, which correlates with recruitment of IL-22-secreting neutrophils at early stages of Citrobacter rodentium infection. Infect. Immun. 83, 3257-3267. doi: 10.1128/IAI.00670-15
68. Lejeune, D., Dumoutier, L., Constantinescu, S., Kruijer, W., Schuringa, J. J., and Renauld, J. C. (2002). Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. J. Biol. Chem. 277, 33676-33682. doi: 10.1074/jbc.M204204200
69. Li, J., Tomkinson, K. N., Tan, X. Y., Wu, P., Yan, G., Spaulding, V., et al. (2004). Temporal associations between interleukin 22 and the extracellular domains of IL-22R and IL-10R2. Int. Immunopharmacol. 4, 693-708. doi: 10.1016/j.intimp.2004.01.010
70. Liang, S. C., Tan, X. Y., Luxenberg, D. P., Karim, R., Dunussi-Joannopoulos, K., Collins, M., et al. (2006). Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271-2279. doi: 10.1084/jem.20061308
71. Littman, D. R., and Rudensky, A. Y. (2010). Th17 and regulatory T cells in mediating and restraining inflammation. Cell 140, 845-858. doi: 10.1016/j.cell.2010.02.021
72. Logsdon, N. J., Jones, B. C., Allman, J. C., Izotova, L., Schwartz, B., Pestka, S., et al. (2004). The IL-10R2 binding hot spot on IL-22 is located on the N-terminal helix and is dependent on N-linked glycosylation. J. Mol. Biol. 342, 503-514. doi: 10.1016/j.jmb.2004.07.069
73. Logsdon, N. J., Jones, B. C., Josephson, K., Cook, J., and Walter, M. R. (2002). Comparison of interleukin-22 and interleukin-10 soluble receptor complexes. J. Interferon Cytokine Res. 22, 1099-1112. doi: 10.1089/10799900260442520
74. Lowe, M. M., Mold, J. E., Kanwar, B., Huang, Y., Louie, A., Pollastri, M. P., et al. (2014). Identification of cinnabarinic acid as a novel endogenous aryl hydrocarbon receptor ligand that drives IL-22 production. PLoS ONE 9:e87877. doi: 10.1371/journal.pone.0087877
75. Luci, C., Reynders, A., Ivanov, I. I., Cognet, C., Chiche, L., Chasson, L., et al. (2009). Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin. Nat. Immunol. 10, 75-82. doi: 10.1038/ni.1681
76. Mabuchi, T., Takekoshi, T., and Hwang, S. T. (2011). Epidermal CCR6+ gammadelta T cells are major producers of IL-22 and IL-17 in a murine model of psoriasiform dermatitis. J. Immunol. 187, 5026-5031. doi: 10.4049/jimmunol.1101817
77. Macdonald, T. T., and Monteleone, G. (2005). Immunity, inflammation, and allergy in the gut. Science 307, 1920-1925. doi: 10.1126/science.1106442
78. Macho-Fernandez, E., Koroleva, E. P., Spencer, C. M., Tighe, M., Torrado, E., Cooper, A. M., et al. (2015). Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells. Mucosal Immunol. 8, 403-413. doi: 10.1038/mi.2014.78
79. Mangan, P. R., Harrington, L. E., O'Quinn, D. B., Helms, W. S., Bullard, D. C., Elson, C. O., et al. (2006). Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441, 231-234. doi: 10.1038/nature04754
80. Mann, E. R., Bernardo, D., Ng, S. C., Rigby, R. J., Al-Hassi, H. O., Landy, J., et al. (2014). Human gut dendritic cells drive aberrant gut-specific t-cell responses in ulcerative colitis, characterized by increased IL-4 production and loss of IL-22 and IFNgamma. Inflamm. Bowel Dis. 20, 2299-2307. doi: 10.1097/MIB.0000000000000223
81. Martin, B., Hirota, K., Cua, D. J., Stockinger, B., and Veldhoen, M. (2009). Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity 31, 321-330. doi: 10.1016/j.immuni.2009.06.020
82. Martin, J. C., Bériou, G., Heslan, M., Bossard, C., Jarry, A., Abidi, A., et al. (2015). IL-22BP is produced by eosinophils in human gut and blocks IL-22 protective actions during colitis. Mucosal Immunol. doi: 10.1038/mi.2015.83. [Epub ahead of print]
83. Martin, J. C., Bériou, G., Heslan, M., Chauvin, C., Utriainen, L., Aumeunier, A., et al. (2014). Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid. Mucosal Immunol. 7, 101-113. doi: 10.1038/mi.2013.28
84. McMillan, B. J., and Bradfield, C. A. (2007). The aryl hydrocarbon receptor is activated by modified low-density lipoprotein. Proc. Natl. Acad. Sci. U.S.A. 104, 1412-1417. doi: 10.1073/pnas.0607296104
85. Mead, P. S., and Griffin, P. M. (1998). Escherichia coli O157:H7. Lancet 352, 1207-1212. doi: 10.1016/S0140-6736(98)01267-7
86. Mebius, R. E., Miyamoto, T., Christensen, J., Domen, J., Cupedo, T., Weissman, I. L., et al. (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, 6593-6601. doi: 10.4049/jimmunol.166.11.6593
87. Mielke, L. A., Jones, S. A., Raverdeau, M., Higgs, R., Stefanska, A., Groom, J. R., et al. (2013). Retinoic acid expression associates with enhanced IL-22 production by gammadelta T cells and innate lymphoid cells and attenuation of intestinal inflammation. J. Exp. Med. 210, 1117-1124. doi: 10.1084/jem.20121588
88. Monteiro, M., Almeida, C. F., Agua-Doce, A., and Graca, L. (2013). Induced IL-17-producing invariant NKT cells require activation in presence of TGF-beta and IL-1beta. J. Immunol. 190, 805-811. doi: 10.4049/jimmunol.1201010
89. Monteleone, I., Rizzo, A., Sarra, M., Sica, G., Sileri, P., Biancone, L., et al. (2011). Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141, 237-248. doi: 10.1053/j.gastro.2011.04.007
90. Moreira-Teixeira, L., Resende, M., Coffre, M., Devergne, O., Herbeuval, J. P., Hermine, O., et al. (2011). Proinflammatory environment dictates the IL-17-producing capacity of human invariant NKT cells. J. Immunol. 186, 5758-5765. doi: 10.4049/jimmunol.1003043
91. Morishima, N., Mizoguchi, I., Takeda, K., Mizuguchi, J., and Yoshimoto, T. (2009). TGF-beta is necessary for induction of IL-23R and Th17 differentiation by IL-6 and IL-23. Biochem. Biophys. Res. Commun. 386, 105-110. doi: 10.1016/j.bbrc.2009.05.140
92. Munneke, J. M., Björklund, A. T., Mjösberg, J. M., Garming-Legert, K., Bernink, J. H., Blom, B., et al. (2014). Activated innate lymphoid cells are associated with a reduced susceptibility to graft-versus-host disease. Blood 124, 812-821. doi: 10.1182/blood-2013-11-536888
93. Muñoz, M., Eidenschenk, C., Ota, N., Wong, K., Lohmann, U., Kühl, A. A., et al. (2015). Interleukin-22 induces interleukin-18 expression from epithelial cells during intestinal infection. Immunity 42, 321-331. doi: 10.1016/j.immuni.2015.01.011
94. Murano, T., Okamoto, R., Ito, G., Nakata, T., Hibiya, S., Shimizu, H., et al. (2014). Hes1 promotes the IL-22-mediated antimicrobial response by enhancing STAT3-dependent transcription in human intestinal epithelial cells. Biochem. Biophys. Res. Commun. 443, 840-846. doi: 10.1016/j.bbrc.2013.12.061
95. Nagalakshmi, M. L., Rascle, A., Zurawski, S., Menon, S., and de Waal Malefyt, R. (2004). Interleukin-22 activates STAT3 and induces IL-10 by colon epithelial cells. Int. Immunopharmacol. 4, 679-691. doi: 10.1016/j.intimp.2004.01.008
96. Naher, L., Kiyoshima, T., Kobayashi, I., Wada, H., Nagata, K., Fujiwara, H., et al. (2012). STAT3 signal transduction through interleukin-22 in oral squamous cell carcinoma. Int. J. Oncol. 41, 1577-1586. doi: 10.3892/ijo.2012.1594
97. Nguyen, L. P., and Bradfield, C. A. (2008). The search for endogenous activators of the aryl hydrocarbon receptor. Chem. Res. Toxicol. 21, 102-116. doi: 10.1021/tx7001965
98. Nurieva, R., Yang, X. O., Martinez, G., Zhang, Y., Panopoulos, A. D., Ma, L., et al. (2007). Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480-483. doi: 10.1038/nature05969
99. Oesch-Bartlomowicz, B., Huelster, A., Wiss, O., Antoniou-Lipfert, P., Dietrich, C., Arand, M., et al. (2005). Aryl hydrocarbon receptor activation by cAMP vs. dioxin: divergent signaling pathways. Proc. Natl. Acad. Sci. U.S.A. 102, 9218-9223. doi: 10.1073/pnas.0503488102
100. Ota, N., Wong, K., Valdez, P. A., Zheng, Y., Crellin, N. K., Diehl, L., et al. (2011). IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium. Nat. Immunol. 12, 941-948. doi: 10.1038/ni.2089
101. Ouyang, W., Rutz, S., Crellin, N. K., Valdez, P. A., and Hymowitz, S. G. (2011). Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol. 29, 71-109. doi: 10.1146/annurev-immunol-031210-101312
102. Pacheco, A. R., Curtis, M. M., Ritchie, J. M., Munera, D., Waldor, M. K., Moreira, C. G., et al. (2012). Fucose sensing regulates bacterial intestinal colonization. Nature 492, 113-117. doi: 10.1038/nature11623
103. Paget, C., Ivanov, S., Fontaine, J., Renneson, J., Blanc, F., Pichavant, M., et al. (2012). Interleukin-22 is produced by invariant natural killer T lymphocytes during influenza A virus infection: potential role in protection against lung epithelial damages. J. Biol. Chem. 287, 8816-8829. doi: 10.1074/jbc.M111.304758
104. Pan, H. F., Li, X. P., Zheng, S. G., and Ye, D. Q. (2013). Emerging role of interleukin-22 in autoimmune diseases. Cytokine Growth Factor Rev. 24, 51-57. doi: 10.1016/j.cytogfr.2012.07.002
105. Paulos, C. M., Carpenito, C., Plesa, G., Suhoski, M. M., Varela-Rohena, A., Golovina, T. N., et al. (2010). The inducible costimulator (ICOS) is critical for the development of human T(H)17 cells. Sci. Transl. Med. 2, 55ra78. doi: 10.1126/scitranslmed.3000448
106. Penel-Sotirakis, K., Simonazzi, E., Péguet-Navarro, J., and Rozières, A. (2012). Differential capacity of human skin dendritic cells to polarize CD4+ T cells into IL-17, IL-21 and IL-22 producing cells. PLoS ONE 7:e45680. doi: 10.1371/journal.pone.0045680
107. Peschon, J. J., Morrissey, P. J., Grabstein, K. H., Ramsdell, F. J., Maraskovsky, E., Gliniak, B. C., et al. (1994). Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J. Exp. Med. 180, 1955-1960. doi: 10.1084/jem.180.5.1955
108. Peterson, L. W., and Artis, D. (2014). Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14, 141-153. doi: 10.1038/nri3608
109. Pham, T. A., Clare, S., Goulding, D., Arasteh, J. M., Stares, M. D., Browne, H. P., et al. (2014). Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen. Cell Host Microbe 16, 504-516. doi: 10.1016/j.chom.2014.08.017
110. Pickard, J. M., Maurice, C. F., Kinnebrew, M. A., Abt, M. C., Schenten, D., Golovkina, T. V., et al. (2014). Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. Nature 514, 638-641. doi: 10.1038/nature13823
111. Pickert, G., Neufert, C., Leppkes, M., Zheng, Y., Wittkopf, N., Warntjen, M., et al. (2009). STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465-1472. doi: 10.1084/jem.20082683
112. Possot, C., Schmutz, S., Chea, S., Boucontet, L., Louise, A., Cumano, A., et al. (2011). Notch signaling is necessary for adult, but not fetal, development of RORgammat(+) innate lymphoid cells. Nat. Immunol. 12, 949-958. doi: 10.1038/ni.2105
113. Puga, A., Ma, C., and Marlowe, J. L. (2009). The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways. Biochem. Pharmacol. 77, 713-722. doi: 10.1016/j.bcp.2008.08.031
114. Qiu, J., Guo, X., Chen, Z. M., He, L., Sonnenberg, G. F., Artis, D., et al. (2013). Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 39, 386-399. doi: 10.1016/j.immuni.2013.08.002
115. Qiu, J., Heller, J. J., Guo, X., Chen, Z. M., Fish, K., Fu, Y. X., et al. (2012). The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92-104. doi: 10.1016/j.immuni.2011.11.011
116. Rachitskaya, A. V., Hansen, A. M., Horai, R., Li, Z., Villasmil, R., Luger, D., et al. (2008). Cutting edge: NKT cells constitutively express IL-23 receptor and RORgammat and rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashion. J. Immunol. 180, 5167-5171. doi: 10.4049/jimmunol.180.8.5167
117. Raifer, H., Mahiny, A. J., Bollig, N., Petermann, F., Hellhund, A., Kellner, K., et al. (2012). Unlike alphabeta T cells, gammadelta T cells, LTi cells and NKT cells do not require IRF4 for the production of IL-17A and IL-22. Eur. J. Immunol. 42, 3189-3201. doi: 10.1002/eji.201142155
118. Rutz, S., Noubade, R., Eidenschenk, C., Ota, N., Zeng, W., Zheng, Y., et al. (2011). Transcription factor c-Maf mediates the TGF-beta-dependent suppression of IL-22 production in T(H)17 cells. Nat. Immunol. 12, 1238-1245. doi: 10.1038/ni.2134
119. Rutz, S., Wang, X., and Ouyang, W. (2014). The IL-20 subfamily of cytokines-from host defence to tissue homeostasis. Nat. Rev. Immunol. 14, 783-795. doi: 10.1038/nri3766
120. Sabat, R., Ouyang, W., and Wolk, K. (2014). Therapeutic opportunities of the IL-22-IL-22R1 system. Nat. Rev. Drug Discov. 13, 21-38. doi: 10.1038/nrd4176
121. Salzman, N. H., and Bevins, C. L. (2013). Dysbiosis-a consequence of Paneth cell dysfunction. Semin. Immunol. 25, 334-341. doi: 10.1016/j.smim.2013.09.006
122. Sanos, S. L., Bui, V. L., Mortha, A., Oberle, K., Heners, C., Johner, C., et al. (2009). RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat. Immunol. 10, 83-91. doi: 10.1038/ni.1684
123. Sanos, S. L., Vonarbourg, C., Mortha, A., and Diefenbach, A. (2011). Control of epithelial cell function by interleukin-22-producing RORgammat+ innate lymphoid cells. Immunology 132, 453-465. doi: 10.1111/j.1365-2567.2011.03410.x
124. Satoh-Takayama, N., Vosshenrich, C. A., Lesjean-Pottier, S., Sawa, S., Lochner, M., Rattis, F., et al. (2008). Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29, 958-970. doi: 10.1016/j.immuni.2008.11.001
125. Sawa, S., Lochner, M., Satoh-Takayama, N., Dulauroy, S., Bérard, M., Kleinschek, M., et al. (2011). RORgammat+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat. Immunol. 12, 320-326. doi: 10.1038/ni.2002
126. Schmechel, S., Konrad, A., Diegelmann, J., Glas, J., Wetzke, M., Paschos, E., et al. (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, 204-212. doi: 10.1002/ibd.20315
127. Sekikawa, A., Fukui, H., Suzuki, K., Karibe, T., Fujii, S., Ichikawa, K., et al. (2010). Involvement of the IL-22/REG Ialpha axis in ulcerative colitis. Lab. Invest. 90, 496-505. doi: 10.1038/labinvest.2009.147
128. Sims, J. E., and Smith, D. E. (2010). The IL-1 family: regulators of immunity. Nat. Rev. Immunol. 10, 89-102. doi: 10.1038/nri2691
129. Sonnenberg, G. F., Fouser, L. A., and Artis, D. (2011a). Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat. Immunol. 12, 383-390. doi: 10.1038/ni.2025
130. Sonnenberg, G. F., Monticelli, L. A., Alenghat, T., Fung, T. C., Hutnick, N. A., Kunisawa, J., et al. (2012). Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321-1325. doi: 10.1126/science.1222551
131. Sonnenberg, G. F., Monticelli, L. A., Elloso, M. M., Fouser, L. A., and Artis, D. (2011b). CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34, 122-134. doi: 10.1016/j.immuni.2010.12.009
132. Souza, J. M., Matias, B. F., Rodrigues, C. M., Murta, E. F., and Michelin, M. A. (2013). IL-17 and IL-22 serum cytokine levels in patients with squamous intraepithelial lesion and invasive cervical carcinoma. Eur. J. Gynaecol. Oncol. 34, 466-468
133. Spits, H., Artis, D., Colonna, M., Diefenbach, A., Di Santo, J. P., Eberl, G., et al. (2013). Innate lymphoid cells-a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145-149. doi: 10.1038/nri3365
134. Spits, H., and Cupedo, T. (2012). Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu. Rev. Immunol. 30, 647-675. doi: 10.1146/annurev-immunol-020711-075053
135. Stelter, C., Käppeli, R., König, C., Krah, A., Hardt, W. D., Stecher, B., et al. (2011). Salmonella-induced mucosal lectin RegIIIbeta kills competing gut microbiota. PLoS ONE 6:e20749. doi: 10.1371/journal.pone.0020749
136. Sugimoto, K., Ogawa, A., Mizoguchi, E., Shimomura, Y., Andoh, A., Bhan, A. K., et al. (2008). IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118, 534-544. doi: 10.1172/jci33194
137. Sun, Z., Unutmaz, D., Zou, Y. R., Sunshine, M. J., Pierani, A., Brenner-Morton, S., et al. (2000). Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science 288, 2369-2373. doi: 10.1126/science.288.5475.2369
138. Sutton, C. E., Lalor, S. J., Sweeney, C. M., Brereton, C. F., Lavelle, E. C., and Mills, K. H. (2009). Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 31, 331-341. doi: 10.1016/j.immuni.2009.08.001
139. Takahashi, A., Wada, A., Ogushi, K., Maeda, K., Kawahara, T., Mawatari, K., et al. (2001). Production of beta-defensin-2 by human colonic epithelial cells induced by Salmonella enteritidis flagella filament structural protein. FEBS Lett. 508, 484-488. doi: 10.1016/S0014-5793(01)03088-5
140. Tortola, L., Rosenwald, E., Abel, B., Blumberg, H., Schäfer, M., Coyle, A. J., et al. (2012). Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk. J. Clin. Invest. 122, 3965-3976. doi: 10.1172/JCI63451
141. Trifari, S., Kaplan, C. D., Tran, E. H., Crellin, N. K., and 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, 864-871. doi: 10.1038/ni.1770
142. Tsuji, M., Suzuki, K., Kitamura, H., Maruya, M., Kinoshita, K., Ivanov, I. I., et al. (2008). Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. Immunity 29, 261-271. doi: 10.1016/j.immuni.2008.05.014
143. Tsuji, N., Fukuda, K., Nagata, Y., Okada, H., Haga, A., Hatakeyama, S., et al. (2014). The activation mechanism of the aryl hydrocarbon receptor (AhR) by molecular chaperone HSP90. FEBS Open Bio 4, 796-803. doi: 10.1016/j.fob.2014.09.003
144. Tumanov, A. V., Koroleva, E. P., Guo, X., Wang, Y., Kruglov, A., Nedospasov, S., et al. (2011). Lymphotoxin controls the IL-22 protection pathway in gut innate lymphoid cells during mucosal pathogen challenge. Cell Host Microbe 10, 44-53. doi: 10.1016/j.chom.2011.06.002
145. Vaishnava, S., Yamamoto, M., Severson, K. M., Ruhn, K. A., Yu, X., Koren, O., et al. (2011). The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255-258. doi: 10.1126/science.1209791
146. van de Veerdonk, F. L., Stoeckman, A. K., Wu, G., Boeckermann, A. N., Azam, T., Netea, M. G., et al. (2012). IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist. Proc. Natl. Acad. Sci. U.S.A. 109, 3001-3005. doi: 10.1073/pnas.1121534109
147. Veldhoen, M., Hirota, K., Westendorf, A. M., Buer, J., Dumoutier, L., Renauld, J. C., et al. (2008). The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106-109. doi: 10.1038/nature06881
148. Volpe, E., Touzot, M., Servant, N., Marloie-Provost, M. A., Hupé, P., Barillot, E., et al. (2009). Multiparametric analysis of cytokine-driven human Th17 differentiation reveals a differential regulation of IL-17 and IL-22 production. Blood 114, 3610-3614. doi: 10.1182/blood-2009-05-223768
149. Vonarbourg, C., Mortha, A., Bui, V. L., Hernandez, P. P., Kiss, E. A., Hoyler, T., et al. (2010). Regulated expression of nuclear receptor RORgammat confers distinct functional fates to NK cell receptor-expressing RORgammat(+) innate lymphocytes. Immunity 33, 736-751. doi: 10.1016/j.immuni.2010.10.017
150. von Freeden-Jeffry, U., Vieira, P., Lucian, L. A., McNeil, T., Burdach, S. E., and Murray, R. (1995). Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med. 181, 1519-1526. doi: 10.1084/jem.181.4.1519
151. Weber, G. F., Schlautkötter, S., Kaiser-Moore, S., Altmayr, F., Holzmann, B., and Weighardt, H. (2007). Inhibition of interleukin-22 attenuates bacterial load and organ failure during acute polymicrobial sepsis. Infect. Immun. 75, 1690-1697. doi: 10.1128/IAI.01564-06
152. Weiss, B., Wolk, K., Grünberg, B. H., Volk, H. D., Sterry, W., Asadullah, K., et al. (2004). Cloning of murine IL-22 receptor alpha 2 and comparison with its human counterpart. Genes Immun. 5, 330-336. doi: 10.1038/sj.gene.6364104
153. Witte, E., Witte, K., Warszawska, K., Sabat, R., and Wolk, K. (2010). Interleukin-22: a cytokine produced by T, NK and NKT cell subsets, with importance in the innate immune defense and tissue protection. Cytokine Growth Factor Rev. 21, 365-379. doi: 10.1016/j.cytogfr.2010.08.002
154. Wolk, K., Kunz, S., Witte, E., Friedrich, M., Asadullah, K., and Sabat, R. (2004). IL-22 increases the innate immunity of tissues. Immunity 21, 241-254. doi: 10.1016/j.immuni.2004.07.007
155. Wolk, K., Witte, E., Hoffmann, U., Doecke, W. D., Endesfelder, S., Asadullah, K., et al. (2007). IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn's disease. J. Immunol. 178, 5973-5981. doi: 10.4049/jimmunol.178.9.5973
156. Wolk, K., Witte, E., Wallace, E., Döcke, W. D., Kunz, S., Asadullah, K., et al. (2006). IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur. J. Immunol. 36, 1309-1323. doi: 10.1002/eji.200535503
157. Wu, P. W., Li, J., Kodangattil, S. R., Luxenberg, D. P., Bennett, F., Martino, M., et al. (2008). IL-22R, IL-10R2, and IL-22BP binding sites are topologically juxtaposed on adjacent and overlapping surfaces of IL-22. J. Mol. Biol. 382, 1168-1183. doi: 10.1016/j.jmb.2008.07.046
158. Xie, M. H., Aggarwal, S., Ho, W. H., Foster, J., Zhang, Z., Stinson, J., et al. (2000). Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J. Biol. Chem. 275, 31335-31339. doi: 10.1074/jbc.M005304200
159. Yoon, S. I., Jones, B. C., Logsdon, N. J., Harris, B. D., Deshpande, A., Radaeva, S., et al. (2010). Structure and mechanism of receptor sharing by the IL-10R2 common chain. Structure 18, 638-648. doi: 10.1016/j.str.2010.02.009
160. Yoshida, H., Honda, K., Shinkura, R., Adachi, S., Nishikawa, S., Maki, K., et al. (1999). IL-7 receptor alpha+ CD3(-) cells in the embryonic intestine induces the organizing center of Peyer's patches. Int. Immunol. 11, 643-655. doi: 10.1093/intimm/11.5.643
161. Zelante, T., Iannitti, R. G., Cunha, C., De Luca, A., Giovannini, G., Pieraccini, G., et al. (2013). Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372-385. doi: 10.1016/j.immuni.2013.08.003
162. Zhang, N., Pan, H. F., and Ye, D. Q. (2011). Th22 in inflammatory and autoimmune disease: prospects for therapeutic intervention. Mol. Cell. Biochem. 353, 41-46. doi: 10.1007/s11010-011-0772-y
163. Zhao, K., Zhao, D., Huang, D., Song, X., Chen, C., Pan, B., et al. (2013). The identification and characteristics of IL-22-producing T cells in acute graft-versus-host disease following allogeneic bone marrow transplantation. Immunobiology 218, 1505-1513. doi: 10.1016/j.imbio.2013.05.005
164. Zhao, K., Zhao, D., Huang, D., Yin, L., Chen, C., Pan, B., et al. (2014). Interleukin-22 aggravates murine acute graft-versus-host disease by expanding effector T cell and reducing regulatory T cell. J. Interferon Cytokine Res. 34, 707-715. doi: 10.1089/jir.2013.0099
165. Zheng, Y., Danilenko, D. M., Valdez, P., Kasman, I., Eastham-Anderson, J., Wu, J., et al. (2007). Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648-651. doi: 10.1038/nature05505
166. Zheng, Y., Valdez, P. A., Danilenko, D. M., Hu, Y., Sa, S. M., Gong, Q., et al. (2008). Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14, 282-289. doi: 10.1038/nm1720
167. Zhou, L., Ivanov, I. I., Spolski, R., Min, R., Shenderov, K., Egawa, T., et al. (2007). IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8, 967-974. doi: 10.1038/ni1488
168. Zhou, L., Lopes, J. E., Chong, M. M., Ivanov, I. I., Min, R., Victora, G. D., et al. (2008). TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453, 236-240. doi: 10.1038/nature06878
169. Zhuang, Y., Peng, L. S., Zhao, Y. L., Shi, Y., Mao, X. H., Guo, G., et al. (2012). Increased intratumoral IL-22-producing CD4(+) T cells and Th22 cells correlate with gastric cancer progression and predict poor patient survival. Cancer Immunol. Immunother. 61, 1965-1975. doi: 10.1007/s00262-012-1241-5
170. Zindl, C. L., Lai, J. F., Lee, Y. K., Maynard, C. L., Harbour, S. N., Ouyang, W., et al. (2013). IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proc. Natl. Acad. Sci. U.S.A. 110, 12768-12773. doi: 10.1073/pnas.1300318110