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.
Authors
- Andrew P. Stewart (ORCID: https://orcid.org/0000-0001-8561-6338)
- Zewen Kelvin Tuong (ORCID: https://orcid.org/0000-0002-6735-6808)
- Katherine Harcourt
- Nathan Richoz (ORCID: https://orcid.org/0000-0002-7422-3237)
- David R. Withers (ORCID: https://orcid.org/0000-0003-3757-7594)
- Rafael Di Marco Barros (ORCID: https://orcid.org/0000-0002-6484-2317)
- Mia Cabantous (ORCID: https://orcid.org/0000-0002-3530-494X)
- Colin Y.C. Lee (ORCID: https://orcid.org/0000-0001-8380-4917)
- Gad Frankel (ORCID: https://orcid.org/0000-0002-0046-1363)
- Ana Peñalver (ORCID: https://orcid.org/0000-0002-5799-6780)
- Menna R. Clatworthy (ORCID: https://orcid.org/0000-0002-3340-9828)
- Anaïs Portet (ORCID: https://orcid.org/0000-0001-7592-0432)
- Eleanor Gillman (ORCID: https://orcid.org/0000-0002-4221-7270)
- Tetsuo Hasegawa (ORCID: https://orcid.org/0000-0001-7737-9491)
- Aaron Fleming (ORCID: https://orcid.org/0000-0002-7909-1579)
- Tammie Tao Min Sow
- David Ruano-Gallego
- Karen Neish
- David A. Posner
- Miles Bremridge (ORCID: https://orcid.org/0009-0003-4344-8243)
- Simon Clare
Institutions
- MRC Laboratory of Molecular Biology (GB)
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- University of Oxford (GB)
- Centro de Biología Molecular Severo Ochoa (ES)
- MRC Epidemiology Unit (GB)
- Molecular Immunity Unit (GB)
- Imperial College London (GB)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2026-09-08
- DOI
- https://doi.org/10.1038/s41593-026-02428-4
- Primary Topic
- Bacterial Infections and Vaccines
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- Medical Research Council