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Peer-reviewedCC BY 4.0Nature Neuroscience

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

  • Aaron Fleming1,2
  • Karen Neish1,2
  • Rafael Di Marco-Barros1,2
  • David A. Posner1,2
  • Colin Y. C. Lee1,2
  • Andrew Stewart1,2
  • Zewen Kelvin Tuong1,2,3
  • Miles Bremridge1,2
  • Ana Peñalver1,2
  • Mia Cabantous1,2
  • Nathan Richoz1,2
  • Anais Portet1,2
9 more authors
  • Katherine Harcourt2,4
  • Eleanor Gillman1,2
  • Tammie Tao Min Sow1,2
  • Tetsuo Hasegawa1,2
  • David Ruano-Gallego5,6
  • Gad Frankel5
  • David Withers7
  • Simon Clare2,4
  • Menna R. Clatworthy1,2,3
7 affiliations
  1. 1Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK
  2. 2Cambridge Institute of Therapeutic Immunology and Infectious Diseases, University of Cambridge, Cambridge, UK
  3. 3Cellular Genetics, Wellcome Sanger Institute, Hinxton, UK
  4. 4Pathogen Genomics, Wellcome Sanger Institute, Hinxton, UK
  5. 5Department of Life Sciences, Imperial College London, London, UK
  6. 6Department of Molecular Biology, Centre of Molecular Biology Severo Ochoa, Madrid, Spain
  7. 7Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK
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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 (TH) 1, TH17 and TH2 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.

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Cite

BibTeXRIS
BibTeX
@article{fleming2026intestinal,
  title = {{Intestinal infections establish antigen-specific, long-lived memory CD4+ T cells in the brain and meninges}},
  author = {Aaron Fleming and Karen Neish and Rafael Di Marco-Barros and David A. Posner and Colin Y. C. Lee and Andrew Stewart and Zewen Kelvin Tuong and Miles Bremridge and Ana Peñalver and Mia Cabantous and Nathan Richoz and Anais Portet and Katherine Harcourt and Eleanor Gillman and Tammie Tao Min Sow and Tetsuo Hasegawa and David Ruano-Gallego and Gad Frankel and David Withers and Simon Clare and Menna R. Clatworthy},
  journal = {Nature Neuroscience},
  year = {2026},
  month = sep,
  doi = {10.1038/s41593-026-02428-4},
  url = {https://doi.org/10.1038/s41593-026-02428-4},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Intestinal infections establish antigen-specific, long-lived memory CD4+ T cells in the brain and meninges
AU  - Aaron Fleming
AU  - Karen Neish
AU  - Rafael Di Marco-Barros
AU  - David A. Posner
AU  - Colin Y. C. Lee
AU  - Andrew Stewart
AU  - Zewen Kelvin Tuong
AU  - Miles Bremridge
AU  - Ana Peñalver
AU  - Mia Cabantous
AU  - Nathan Richoz
AU  - Anais Portet
AU  - Katherine Harcourt
AU  - Eleanor Gillman
AU  - Tammie Tao Min Sow
AU  - Tetsuo Hasegawa
AU  - David Ruano-Gallego
AU  - Gad Frankel
AU  - David Withers
AU  - Simon Clare
AU  - Menna R. Clatworthy
PY  - 2026
DA  - 2026/09/08
JO  - Nature Neuroscience
DO  - 10.1038/s41593-026-02428-4
UR  - https://doi.org/10.1038/s41593-026-02428-4
AB  - 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 (TH) 1, TH17 and TH2 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.
SN  - 1097-6256
SN  - 1546-1726
ER  -