title: Generation and function of immunosuppressive human and murine CD8+ T cells by transforming growth factor-β and retinoic acid.
abstract: The intestinal immune system is constantly challenged by foreign antigens and commensal bacteria. Therefore, proper control of the intestinal microenvironment is required. One important arm of this regulatory network consists of regulatory T cells. In contrast to CD4(+) Foxp3(+) regulatory T cells, which have been well characterized, immunomodulatory CD8(+) T cells that express Foxp3 are less well defined in terms of their generation and function. Failures of these regulatory mechanisms contribute to the development of inflammatory bowel disease. In this study we demonstrate that the frequency of CD8(+) Foxp3(+) T cells is reduced in the peripheral blood of patients with ulcerative colitis. As these cells might play a currently underestimated role in the maintenance of intestinal homeostasis, we have investigated human and murine CD8(+) Foxp3(+) T cells generated by stimulating naive CD8(+) T cells in the presence of transforming growth factor-β and retinoic acid, mediators that are abundantly produced in the intestinal mucosa. These CD8(+) Foxp3(+) fully competent regulatory T cells show strong expression of regulatory molecules CD25, Gpr83 and CTLA-4 and exhibit cell-cell contact-dependent immunosuppressive activity in vitro. Our study illustrates a previously unappreciated critical role of CD8(+) Foxp3(+) T cells in controlling potentially dangerous T cells and in the maintenance of intestinal homeostasis.
authors.affiliation: Institute of Medical Microbiology, University Hospital, University Duisburg-Essen, Essen.
authors.forename: Diana
authors.initials: D
authors.lastname: Fleissner
authors.forename: Annika
authors.initials: A
authors.lastname: Frede
authors.forename: Markus
authors.initials: M
authors.lastname: Knott
authors.forename: Torben
authors.initials: T
authors.lastname: Knuschke
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.forename: Wiebke
authors.initials: W
authors.lastname: Hansen
authors.forename: Gustav
authors.initials: G
authors.lastname: Dobos
authors.forename: Jost
authors.initials: J
authors.lastname: Langhorst
authors.forename: Jan
authors.initials: J
authors.lastname: Buer
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Westendorf
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D060908:CTLA-4 Antigen; D002450:Cell Communication / Q000276:immunology; D002452:Cell Count; D049109:Cell Proliferation; D018920:Coculture Techniques; D003093:Colitis, Ulcerative / Q000276:immunology / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D053804:Granzymes / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D052899:Pore Forming Cytotoxic Proteins; D016212:Transforming Growth Factor beta; C483886:perforin, mouse; D049452:Green Fluorescent Proteins; D014212:Tretinoin; D007371:Interferon-gamma; D053804:Granzymes