Multi-step Th17 differentiation in response to segmented filamentous bacteria in the mouse intestine

Abstract

Abstract Th17 cells have significant roles in maintaining homeostasis and regulating host defense against various pathogens in our bodies. Our laboratory initially identified segmented filamentous bacteria (SFB) as a unique commensal that is sufficient for Th17 cell differentiation and promotion of Th17-dependent autoimmune diseases such as a mouse model of spontaneous arthritis. The molecular and cellular requirements of SFB-induced Th17 cell differentiation are still unclear. To understand the whole process of Th17 cells differentiation in vivo, we developed SFB-specific T cell receptor transgenic (7B8) mice. We can trace SFB-specific Th17 cell differentiation and response by transferring fluorescently-labeled 7B8 naïve T cells into SFB-gavaged host mice. Using this approach, we have elucidated the requirements for cytokines and antigen presenting cells (APCs) to understand the process of Th17 cell differentiation. Here, we describe that initial induction and expansion of Th17 cells occurs in mesenteric lymph nodes (MLN), and their subsequent migration to intestine is integrin β7-dependent. Although RORγt expression in Th17 cells is mainly dependent on IL-6 signaling in the MLN, IL-23R signaling also contributes to RORγt expression in Th17 cells in the ileum in the absence of IL-6. CD103+ CD11b+ APCs are not important for induction and initial expansion of SFB-specific Th17 cells in MLN, but play important roles in maintenance of SFB-specific Th17 cells in the ileum. Taken together, these results indicate that Th17 cell differentiation proceeds in multiple discrete stages.