Gut inflammation promotes microbiota-specific CD4 T cell-mediated neuroinflammation.

Abstract

The microbiota has been recognized as a critical contributor to various diseases¹, with multiple reports of changes in the composition of the gut microbiome in contexts such as inflammatory bowel disease^2,3 and neurodegenerative diseases⁴. These microbial shifts can exert systemic effects by altering the release of specific metabolites into the bloodstream^5,6, and the gastrointestinal microbiota has also been reported to exhibit immunomodulatory activity through the activation of innate and adaptive immunity^7,8. However, it remains unclear how the microbiota contributes to inflammation in the central nervous system (CNS), where these microorganisms are typically absent. Here we report that T cells that recognize gut-colonizing segmented filamentous bacteria can induce inflammation in the mouse intestine and CNS in the absence of functional regulatory T cells. Gut commensal-specific CD4 T cells (T_comm cells) that are dysregulated in the inflamed gut can become licensed to infiltrate into the CNS regardless 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, IFNγ and IL-17A, triggering neurological damage. These infiltrated T_comm cells initiate CNS inflammation by activating microglia through their IL-23R-dependent encephalitogenic programme and their IL-23R-independent GM-CSF production. Together, our findings reveal potential mechanisms whereby perturbation of T_comm cells can contribute to extraintestinal inflammation.