B-lymphocyte induced maturation protein 1 (Blimp-1) is required to limit the number of IL17A-producing CD4+ T cells in vivo. (P1139)

Abstract

Abstract Blimp-1 is a transcription factor required for embryonic development and immunity. Mice with T-cell-specific deletion of Blimp-1 (Blimp-1CKO) develop severe intestinal inflammation apparently mediated by CD4+Th cells, but little is known about Blimp-1’s role in regulating Th cell differentiation in vivo. Here we show that Blimp-1 restrains Th cell production of IL17 and IFNγ in vivo. Blimp-1CKO mice accumulate IL17 and IFNγ-producing TCRβ+CD4+cells in lymphoid organs and intestinal mucosa. Increased numbers of IL17-producing Th cells are also observed in WT and Blimp-1CKO-mixed BM chimeric mice containing WT regulatory T (treg) cells, suggesting a Treg-independent intrinsic role for Blimp-1 in constraining IL17production. Blimp-1-/-naïve CD4+Tcells are more prone to differentiate into IL17+IFNγ+ cells and cause severe colitis when transferred to Rag1-/- mice. In vitro-stimulated Blimp-1-/- CD4+T cells show increased expression of il17a and other Th17-related genes, suggesting that Blimp-1 could inhibit transcription of Th17 genes. Using ChIP assays we identified at least one site at the il17a gene that can be bound by Blimp-1 in Th cells, suggesting that Blimp-1 could function as a direct repressor of il17a. Single cell analysis reveals that Blimp-1 expression is selectively regulated during Th differentiation and directly correlates with suppression of Th17 traits in Th1cells. Collectively, these results establish a new role for Blimp-1 in regulating IL17 production in vivo