Intestinal infections establish antigen-specific, long-lived memory CD4+ T cells in the brain and meninges

Abstract The meninges form the border between the brain and periphery and house a rich network of immune cells. Here we show that gastrointestinal challenges (intracellular or extracellular bacteria and parasites) reshape the nature of CD4 + T cells in the dura mater, the outer meningeal layer, changing the dominant polarization states to T helper (T H ) 1, T H 17 and T H 2 cells, respectively, with differing cytokine profiles. This occurs via CXCR6–CXCL16-dependent migration of gut-activated CD4 + T cells to the central nervous system, where they establish long-lived memory populations around the dural venous sinuses, within dural lymphoid aggregates and in the brain. Functionally, these orally primed dural CD4 + T were capable of rapid, antigen-specific recall responses, proliferating and producing cytokines upon intravenous rechallenge. Our findings reveal a direct link between intestinal and dural immunity, enabling the central nervous system borders to acquire immunological memory of gut microorganisms, a major source of bloodborne pathogens capable of reaching the brain via fenestrated dural vasculature.