The gut microbiota has been implicated in many autoimmune diseases, both inside and outside the gut (gut- distal/systemic). However, how bacteria that reside in the gut affect the gut-distal diseases remains largely unknown. Significant insights have been gained from studying the interactions of several specific commensals, including segmented filamentous bacteria (SFB), and the host. These commensals can affect certain T cell subtype(s) including T helper 1 (Th1), Th17, and regulatory T cells (Tregs). However, almost nothing is known about how or which commensals impact T follicular helper (Tfh) cells. Tfh cells are a crucial T cell type that helps B cells produce high-affinity antibodie (Abs) in the germinal center (GC). However, an overactive Tfh cell response can lead to autoimmunity. We have established a new and more physiologically relevant platform to study the commensal effect by introducing SFB into specific-pathogen-free (SPF) (rather than germ-free, our old approach) K/BxN autoimmune arthritis mice, whose disease mechanism relies on Tfh cells and auto-Abs. As in GF mice, SFB strongly enhances disease and auto-Ab production in SPF K/BxN mice. Notably, our preliminary data indicate a role for SFB in Tfh cells, as an increase in the Tfh and GC cell populations was observed in SFB (+) compared to SFB (-) K/BxN mice. To our knowledge, this is the first data showing an association of a specific commensal type to Tfh cells. Therefore, we hypothesize that gut microbiota can drive gut-distal autoimmune disease by enhancing the Tfh cell response. We will: 1) assess the mechanism for SFB- dependent expansion of systemic Tfh cells;2) test whether SFB increases auto-Ab production by inducing Tfh cell cytokines or reprogramming other Th subtypes into Tfh cells;and 3) assess whether the gut can serve as a Tfh priming site, which is required for the systemic (splenic) Tfh cell response. We will determine whether SFB increases Tfh cells by enhancing proliferation, survival, and/or differentiation. We will use retroviral systems to see if overexpression of SFB-dependent cytokines can correct the defects of auto-Ab induction in SFB (-) K/BxN Tfh cells. We will also test whether SFB enhances auto-Ab production by increasing Tfh cells through reprogramming of other Th subtypes (in vitro skewed or ex-vivo isolated). Our new data show a tremendous SFB-dependent increase in Tfh cells in the gut Peyer's patch (PP). We expect to see the PP Tfh response occur earlier than the splenic Tfh response, suggesting that the gut, rather than the spleen, is the Tfh priming site. We will examine the role of gut Tfh cells in the splenic Tfh response by generating K/BxN mice that are gut-lymphoid-tissue deficient. We anticipate that SFB will no longer enhance the splenic Tfh response in K/BxN mice with a gut Tfh deficiency. Studying the commensal effect on Tfh cells will have crucial impacts on public health, as dysbiosis caused by modern medical practice might trigger autoimmunity by affecting Tfh cells. This proposal will help us understand the pathogenesis of autoimmunity and provide new foundations for novel therapies.!
This proposal will increase our understanding of a crucial but inadequately investigated scientific area: how gut commensal bacteria alter the development of a gut-distal (systemic) autoimmune disease by affecting the host's immunity. We will tackle this question by performing mechanistic studies on 1) how gut commensal bacteria can augment gut-distal autoimmunity by enhancing the response of T follicular helper cells, a key T subtype known to provide B cell help;2) how the gut commensal-mediated intestinal immune response contributes to gut-distal autoimmunity. The results of these mechanistic studies will have crucial impacts on public health, as they will pave the way to generate novel immune- or microbe- based therapies for dysbiosis- related immune disorders that have being rising sharply in the industrialized world.
|Teng, Fei; Klinger, Christina N; Felix, Krysta M et al. (2016) Gut Microbiota Drive Autoimmune Arthritis by Promoting Differentiation and Migration of Peyer's Patch T Follicular Helper Cells. Immunity 44:875-88|