Defining the molecular and cellular mechanisms of gut commensal microbiota-specific T cell-mediated intestinal- and neuro-inflammation

About This Grant

Project Summary: Gut commensal bacteria are key regulators of normal tissue homeostasis and the development and exacerbation of multiple autoimmune diseases. However, it remains unclear how the intestinal microbiota contributes to inflammation in distal tissues such as the central nervous system (CNS) in which these microbes are typically absent. Our previous work have focused on how commensal-specific CD4 T cells can be generated in response to the immunogenic commensal bacterial species using mouse lines and germ-free (GF)/gnotobiotic approachs. Our published papers and on-going projects suggest that one of the immunogenic mouse gut commensal, segmented filamentous bacteria (SFB)-specific T cells are initially generated in the gut-draining mesenteric lymph nodes (mLN)s and intestines in response to SFB-derived antigens, resulting in SFB-specific CD4 T cells (SFB TCR7B8 CD4 T cells) subsequently being reactivated in response to peptides derived from host proteins in the CNS via molecular mimicry, leading to autoimmune neuroinflammation. SFB TCR7B8 can induce intestinal inflammation and infiltrate the CNS wherein they can be reactivated and produce inflammatory cytokines including IFNg, IL-17A, and GM-CSF via molecular mimicry owing to their re-stimulation by cross-reactive host- derived proteins in the CNS. However, the molecular and cellular mechanisms by which TCR7B8 CD4 T cells can become dysregulated, be re-stimulated, obtain encephalitogenicity, and induce damage winthin the CNS are largely unknown. In this study, our goal is to control gut commensal-specific CD4 T cell-mediated autoimmune CNS inflammation using an SFB-specific TCR Tg system as a model of commensal-specific T cell-mediated CNS inflammation. To achieve our goal, we propose three Aims; In Aim 1, we will elucidate the pathogenic roles of cell-cell communication among TCR7B8 CD4 T cells, microglia/macrophages, and neuronal cells during TCR7B8-mediated autoimmune CNS inflammation. In Aim 2, we will investigate the regulatory mechanisisms for suppressing TCR7B8-mediated CNS inflammation. For this, we will test when, where, and how regulatory T cells can suppress the autoimmune CNS inflammation. In Aim 3, we will explore the possibility of the gut-brain axis-induced CNS inflammation beyond SFB-specific TCR7B8-mediated molecular mimicry CNS inflammation. Overall, our proposed study will offer new insight into the mechanisms governing gut commensal-induced autoimmunity, with an understanding of how gut T cells can migrate into and obtain encephalitogenicity within the CNS being particularly critical to the design of novel treatments for T cell-mediated autoimmune neuroinflammation and other autoimmune and immune-mediated inflammatory diseases.