Commensal-specific CD4 T cells can promote inflammation in the central nervous system via molecular mimicry

Abstract

Abstract Commensal bacteria are critical regulators of both tissue homeostasis and the development and exacerbation of autoimmunity. However, it remains unclear how the intestinal microbiota contributes to inflammation in tissues such as the central nervous system (CNS) where these microbes are typically absent and whether T cell receptor (TCR) specificity for commensal-derived antigens is important to the development of tissue inflammation-related outcomes. Here, we found that ileum- and cecum-colonizing segmented filamentous bacteria (SFB)-specific T cells (clone TCR 7B8) can infiltrate the CNS wherein they can be reactivated and produce high levels of inflammatory cytokines including IFNγ, IL-17A, TNFα, and GM-CSF in the absence of regulatory T cells. In contrast, other SFB-specific T cells (clone TCR 1A2) recognizing an epitope in which 8/9 amino acids overlap with those recognized by TCR 7B8failed to induce such neuroinflammation. Despite their similar SFB-derived peptide antigen targets, TCR 7B8was found to recognize peptides derived from host proteins including receptor tyrosine-protein kinase ErbB2, trophinin 1, and anaphase-promoting complex subunit 2 in vitro, whereas TCR 1A2did not, indicating that TCR 7B8induces CNS inflammation via molecular mimicry. Immune checkpoint blockade accelerated TCR 7B8-mediated CNS inflammation. Together, our findings reveal a potential mechanism whereby gut commensal-specific T cells are dysregulated, infiltrate into the CNS, and contribute to extraintestinal inflammation. Supported by grants from UIC start-up funds and UIC COVID Relief Funding.