title: B lymphocyte-induced maturation protein-1 contributes to intestinal mucosa homeostasis by limiting the number of IL-17-producing CD4+ T cells.
abstract: The transcription factor B lymphocyte-induced maturation protein-1 (Blimp-1) plays important roles in embryonic development and immunity. Blimp-1 is required for the differentiation of plasma cells, and mice with T cell-specific deletion of Blimp-1 (Blimp-1CKO mice) develop a fatal inflammatory response in the colon. Previous work demonstrated that lack of Blimp-1 in CD4(+) and CD8(+) T cells leads to intrinsic functional defects, but little is known about the functional role of Blimp-1 in regulating differentiation of Th cells in vivo and their contribution to the chronic intestinal inflammation observed in the Blimp1CKO mice. In this study, we show that Blimp-1 is required to restrain the production of the inflammatory cytokine IL-17 by Th cells in vivo. Blimp-1CKO mice have greater numbers of IL-17-producing TCRβ(+)CD4(+)cells in lymphoid organs and in the intestinal mucosa. The increase in IL-17-producing cells was not restored to normal levels in wild-type and Blimp-1CKO-mixed bone marrow chimeric mice, suggesting an intrinsic role for Blimp-1 in constraining the production of IL-17 in vivo. The observation that Blimp-1-deficient CD4(+) T cells are more prone to differentiate into IL-17(+)/IFN-γ(+) cells and cause severe colitis when transferred to Rag1-deficient mice provides further evidence that Blimp-1 represses IL-17 production. Analysis of Blimp-1 expression at the single cell level during Th differentiation reveals that Blimp-1 expression is induced in Th1 and Th2 but repressed by TGF-β in Th17 cells. Collectively, the results described here establish a new role for Blimp-1 in regulating IL-17 production in vivo.
authors.affiliation: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Soofia
authors.initials: S
authors.lastname: Salehi
authors.forename: Rashmi
authors.initials: R
authors.lastname: Bankoti
authors.forename: Luciana
authors.initials: L
authors.lastname: Benevides
authors.forename: Jessica
authors.initials: J
authors.lastname: Willen
authors.forename: Michael
authors.initials: M
authors.lastname: Couse
authors.forename: Joao S
authors.initials: JS
authors.lastname: Silva
authors.forename: Deepti
authors.initials: D
authors.lastname: Dhall
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
authors.forename: Stephan
authors.initials: S
authors.lastname: Targan
authors.forename: Gislâine A
authors.initials: GA
authors.lastname: Martins
mesh_terms: D000818:Animals; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017930:Genes, Reporter / Q000276:immunology; D006706:Homeostasis / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000074462:Positive Regulatory Domain I-Binding Factor 1; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology*
chemical_list: D020381:Interleukin-17; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1