Alterations to the gut microbiota have been associated with a range of extraintestinal diseases through various potential pathways. One such pathway involves T cells activated by the gut microbiota, which can enter the systemic circulation and could contribute to inflammation in other tissues including the central nervous system (CNS). However, the mechanisms by which microbiota-specific T cells might infiltrate and cause inflammation in distal tissues such as the CNS are unclear. White et al. show that CD4+ T cells specific for segmented filamentous bacteria (SFB) can enter the CNS following gut inflammation and can cross-react with self-antigens in the CNS to mediate neuroinflammation.

To show that SFB colonization is necessary for T cell-mediated CNS inflammation, Rag2–/– hosts were treated with ampicillin before TCR7B8 T cell transfer, which prevented neurological symptoms from developing. By contrast, Rag2–/– hosts mono-colonized with SFB and kept in a germ-free isolator had TCR7B8 T cells in the CNS and neurological disease after T cell transfer. Further experiments also showed the requirement for gut inflammation to mediate T cell infiltration of the CNS. TCR7B8 T cells that lack β7 integrin and have reduced migration from lymph nodes to the intestinal lamina propria induced less CNS inflammation. Furthermore, modulating the levels of gut inflammation — using immune checkpoint blockade (ICB) or depletion of Treg cells in Rag2-sufficient mice — also modulated levels of CNS inflammation and neurological phenotypes after TCR7B8 T cell transfer.