Intestinal inflammation promotes gut commensal-specific CD4 T cell to initiate molecular mimicry-mediated neuroinflammation
The microbiota has been recognized as a critical contributor to various diseases, with multiple reports of changes in the composition of the gut microbiome in the context of not only inflammatory bowel disease (IBD), but also neurodegenerative diseases. These microbial shifts can exert systemic effects by altering the release of specific metabolites into the bloodstream, and the gastrointestinal microbiota has further been reported to exhibit immunomodulatory activity through the activation of innate and adaptive immunity. However, it remains unclear how the intestinal microbiota contributes to inflammation in the central nervous system (CNS), where these microorganisms are typically absent. Here, we report that ileum- and cecum-colonizing segmented filamentous bacteria (SFB)-specific T cells can induce inflammation in both the intestines and the CNS. Commensal-specific CD4 T cells that are dysregulated in the inflamed gut can become licensed to infiltrate into the CNS irrespective of their antigen specificity and have the potential to be re-stimulated by host protein-derived antigens in the CNS via molecular mimicry, whereupon they produce high levels of GM-CSF, TNFa, IFNg, and IL-17A, triggering neurological damage. We find that these infiltrated commensal-specific CD4 T cells initiate CNS inflammation by activating microglia through their IL-23R dependent encephalitogenic program and their IL-23R-independent GM-CSF production. Together, our findings reveal a potential mechanism whereby perturbation of commensal-specific T cells can contribute to extraintestinal inflammation. Overall design: To ascertain the contribution of microglia in the TCR7B8-mediated CNS inflammation, we depleted microglia and macrophages by supplementing CSF1R inhibitor (PLX5622) into the normal mouse food. The sorted 1.0 x 105 cells of CD4-TdTomato+ Csf-2- (GM-CSF)-sufficient or -deficient TCR7B8 naïve CD4 T cells were retro-orbitally injected into adult SFB-colonizing Rag2-/- (6 weeks-old) mice. Four days following the naïve CD4 T cell transfer, PLX5622-formulated AIN-67A or AIN-67A as a control were provided. Fresh diets were provided every week for 6 weeks. At 6 weeks following the naïve T cell transfer, the brainstem, thalamus, and hypothalamus—regions characterized by robust CD4? T cell infiltration and activated microglia—were dissected and cells in the indicated tissues were collected for single cell transcriptomic analysis.