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-1 CKO 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 T helper (h) cells in vivo and their contribution to the chronic intestinal inflammation observed in the Blimp1CKO mice. Here we show that Blimp-1 is required to restrain the production of the inflammatory cytokine IL17 by Th cells in vivo. Blimp-1CKO mice have greater numbers of IL17-producing TCRβ+CD4+cells in lymphoid organs and in the intestinal mucosa. The increase in IL17-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 IL17 in vivo. The observation that Blimp-1-deficient CD4+ T cells are more prone to differentiate into IL17+/IFNγ+ cells and cause severe colitis when transferred to Rag1-deficient mice provides further evidence that Blimp-1 represses IL17 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 TGFβ in Th17 cells. Collectively, the results described here establish a new role for Blimp-1 in regulating IL17 production in vivo.

The transcriptional regulator Blimp1 plays crucial roles in controlling terminal differentiation in several lineages. In T cells, Blimp1 is expressed in both effector (Teff) and regulatory (Treg) cells, and mice with T cell-specific deletion of Blimp1 (Blimp1CKO mice) spontaneously develop severe intestinal inflammation, indicating a crucial role for Blimp1 in T cell homeostasis regulation. Blimp1 has been shown to function as a direct activator of the Il10 gene and although its requirement for IL10 expression has been demonstrated in both Treg and Teff cells under inflammatory conditions, the intrinsic requirement of Blimp1 for homeostatic maintenance of these T cell subsets had not been investigated. Using mice with Foxp3+ Treg-cell specific deletion of Blimp1 and other approaches, here we show that Foxp3+ Treg cell-intrinsic expression of Blimp1 is required to control Treg and Teff cells homeostasis but, unexpectedly, it is dispensable to prevent development of severe spontaneous intestinal inflammation. In addition, we show that Blimp1 controls common and unique aspects of Treg and Teff cell function by differentially regulating gene expression in these T cell subsets. These findings document previously unappreciated aspects of Blimp1’s role in T cell biology and shed light on the intricate mechanisms regulating Treg and Teff cell function.

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