Intestinal challenges shape the polarisation of protective dural memory CD4 T cells

Fleming, A.; Di Marco-Barros, R.; Posner, D. A.; Lee, C. Y.; Stewart, A.; Tuong, Z. K.; Neish, K.; Penalver, A.; Cabantous, M.; Richoz, N.; Portet, A.; Harcourt, K.; Gillman, E.; Ruano-Gallego, D.; Frankel, G.; Withers, D.; Clare, S.; Clatworthy, M. R.

doi:10.1101/2025.09.09.673536

bioRxiv · 10.1101/2025.09.09.673536

Intestinal challenges shape the polarisation of protective dural memory CD4 T cells

Fleming, A.·Di Marco-Barros, R.·Posner, D. A.·Lee, C. Y.·Stewart, A.·Tuong, Z. K.·Neish, K.·Penalver, A.·Cabantous, M.·Richoz, N.·Portet, A.·Harcourt, K.·Gillman, E.·Ruano-Gallego, D.·Frankel, G.·Withers, D.·Clare, S.·Clatworthy, M. R.

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Abstract

The meninges house several innate and adaptive immune cell populations1-3. These predominantly localise within the dura mater and include gut-derived IgA-secreting plasma cells4. Whether T cell adaptive memory in the dura is similarly linked to the gut is currently unknown. Here we show that dural CD4 T cell polarisation to a T helper (Th) 1, Th2 and Th17 state is determined by the nature of the immunological challenge encountered in the gastrointestinal tract. We find that intestinally polarised CD4 T cells seed to the dura in a CXCR6-CXCL16-dependent manner, express tissue-residency markers and are long-lived. Functionally, these orally-primed dural CD4 T are capable of a rapid antigen-specific recall response that limits pathogen spread into the brain following intravenous re-challenge. Our work reveals how linked intestinal and dural immunity enables the central nervous system to accrue immunological memory of gut microbes, the most likely source of life-threatening bloodborne pathogens.

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Fleming, A., Di Marco-Barros, R., Posner, D. A., Lee, C. Y., Stewart, A., Tuong, Z. K., Neish, K., Penalver, A., Cabantous, M., Richoz, N., Portet, A., Harcourt, K., Gillman, E., Ruano-Gallego, D., Frankel, G., Withers, D., Clare, S., Clatworthy, M. R.. 2025-09-12. Intestinal challenges shape the polarisation of protective dural memory CD4 T cells. https://doi.org/10.1101/2025.09.09.673536

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