Characterizing regulatory T cell differentiation to bacterial antigens in the gut (MUC8P.727)

Abstract

Abstract Regulatory T cells are an essential component of immune tolerance towards gut bacteria. Conversely, the microbiota shape the colonic Treg population. However, it is unclear if and how commensal bacteria direct naïve T cells to become peripheral Treg (pTreg) cells. Here, we define the process of pTreg development using transgenic T cells expressing commensal antigen reactive TCRs isolated from colonic Treg cells. We show that naïve TCR transgenic cells transferred into lymphoreplete mice are initially activated in a specific distal mesenteric lymph node. Treg cell differentiation is rapid, starting within 3 days, and efficient, with over 50% Foxp3+ cells arising 1 week after transfer. Contrary to prior observations, Foxp3+ cells are the most divided cells, suggesting that Treg cell differentiation is the primary cell fate upon commensal antigen encounter for these T cells. The most efficient period of Treg cell differentiation in TCR transgenic cells is around the age of weaning. Although T cells deficient in CNS1 showed a marked block in early Treg cell selection, dnTGFβRII cells were only partially deficient in Treg cell generation 1 week after transfer. By contrast, CNS1-deficient cells can upregulate Foxp3 at later time points. Thus, these data illustrate the kinetics, geography, and robustness of peripheral Treg cell selection to commensal bacteria, and suggests that CNS1 is an important region involved in early Foxp3 induction in a relatively TGFβ-independent fashion.