title: CD69 regulates type I IFN-induced tolerogenic signals to mucosal CD4 T cells that attenuate their colitogenic potential.
abstract: CD69 is highly expressed by lymphocytes at mucosal surfaces. We aimed to investigate the role of CD69 in mucosal immune responses. The expression of CD69 by CD4 T cells isolated from the spleen, mesenteric lymph nodes, small intestinal lamina propria, and colonic lamina propria was determined in specific pathogen-free B6 and TCR transgenic animals, as well as in germ-free B6 mice. Transfer colitis was induced by transplanting RAG(-/-) mice with B6 or CD69(-/-)CD45RB(high) CD4 T cells. CD69 expression by CD4 T cells is induced by the intestinal microflora, oral delivery of specific Ag, and type I IFN (IFN-I) signals. CD4 T cells from CD69(-/-) animals produce higher amounts of the proinflammatory cytokines IFN-γ, TNF-α, and IL-21, whereas the production of TGF-β1 is decreased. CD69-deficient CD4 T cells showed reduced potential to differentiate into Foxp3(+) regulatory T cells in vivo and in vitro. The transfer of CD69(-/-)CD45RB(high) CD4 T cells into RAG(-/-) hosts induced an accelerated colitis. Oral tolerance was impaired in CD69(-/-) and IFN-I receptor 1-deficient mice when compared with B6 and OT-II × RAG(-/-) animals. Polyinosinic-polycytidylic acid treatment of RAG(-/-) mice transplanted with B6 but not CD69(-/-) or IFN-I receptor 1-deficient CD45RB(high) CD4 T cells attenuated transfer colitis. CD69 deficiency led to the increased production of proinflammatory cytokines, reduced Foxp3(+) regulatory T cell induction, impaired oral tolerance, and more severe colitis. Hence, the activation Ag CD69 plays an important role in regulating mucosal immune responses.
authors.affiliation: Department of Internal Medicine I, University of Ulm, Ulm D-89081, Germany.
authors.forename: Katarina
authors.initials: K
authors.lastname: Radulovic
authors.forename: Calin
authors.initials: C
authors.lastname: Manta
authors.forename: Valerio
authors.initials: V
authors.lastname: Rossini
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Holzmann
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kestler
authors.forename: Ursula Maria
authors.initials: UM
authors.lastname: Wegenka
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
authors.forename: Jan Hendrik
authors.initials: JH
authors.lastname: Niess
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D003092:Colitis / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D018928:Immunity, Mucosal; D007370:Interferon Type I / Q000378:metabolism*; D007371:Interferon-gamma / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009092:Mucous Membrane / Q000276:immunology; D011070:Poly I-C / Q000008:administration & dosage / Q000494:pharmacology; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000098546:Interleukin-21; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D051858:Forkhead Transcription Factors; D007370:Interferon Type I; D007371:Interferon-gamma; D007378:Interleukins; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens; D011070:Poly I-C; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D000098546:Interleukin-21; D000099192:CD69 Antigens; C498833:Foxp3 protein, mouse