Regulation of intestinal TH17 cell pathogenicity by commensal microbiota

TH17 cells are an essential part of the intestinal immune system. TH17 cells play important role in maintaining barrier integrity and are present in the intestinal lamina propria at steady state even in the absence of inflammation. However, TH17 cells can also be important drivers of intestinal inflammation during IBD. Thus, TH17 cells can be friend or foe. The mechanisms establishing beneficial or pathogenic properties of TH17 cells are not fully understood. During IBD, invasion of intestinal bacteria following damage of the intestinal epithelial barrier is thought to induce differentiation of pathogenic TH17 cells. Epithelial damage, and induction of inflammatory TH17 cells against luminal bacteria are drivers of pathology in IBD. Therefore, identifying factors responsible for increasing or restraining pathogenicity of intestinal TH17 cell is of direct clinical interest. It is now known that certain commensal bacteria, such as segmented filamentous bacteria (SFB), have the ability to induce TH17 cells under homeostatic conditions without causing tissue damage or intestinal inflammation. However, it is not known whether commensal-specific TH17 cells, induced under homeostatic conditions, have pathogenic or protective properties. Here, we propose to examine the transcriptional regulation, stability, and pathogenic potential of commensal-specific TH17 cells in laboratory mice. Furthermore, we will examine whether similar populations of intestinal TH17 cells exist in healthy humans. Our overall hypothesis is that commensal-specific TH17 cells are distinct from inflammatory TH17 cells. More specifically, we hypothesize that commensal-specific TH17 cells, which are induced under homeostatic conditions in the intestine, have non-pathogenic tissue protective functions. We will examine the following specific aims: 1) We will analyze the cytokine expression profiles and the expression of co-inhibitory receptors on commensal-specific TH17 cells. Furthermore, we will compare the complete transcriptional programs of commensal-specific TH17 cells and inflammatory TH17 cells by performing next generation sequencing; 2) We will directly assess the pathogenic potential of commensal-specific TH17 cells in animal models of IBD; 3) We will examine the heterogeneity and transcriptional profiles of human intestinal TH17 cells from healthy donors.