2. Academic Validation
  3. Gut inflammation promotes microbiota-specific CD4 T cell-mediated neuroinflammation

Gut inflammation promotes microbiota-specific CD4 T cell-mediated neuroinflammation

  • Nature. 2025 Jul;643(8071):509-518. doi: 10.1038/s41586-025-09120-w.
Zachary White 1,  Ivan Cabrera 1,  Linghan Mei 2,  Margarette Clevenger 2,  Andrea Ochoa-Raya 1,  Isabel Kapustka 1,  Joseph R Dominguez 3,  Jinyan Zhou 4,  Kevin P Koster 5,  Shehata Anwar 4 6,  Qianxun Wang 1,  Charles Ng 7,  Shoko Sagoshi 5,  Takashi Matsuo 1,  Dulari Jayawardena 8,  Seung Hyeon Kim 3,  Takahiro Kageyama 1,  Benjamin J Mitchell 1,  Dante Rivera 1,  Pradeep K Dudeja 1 8 9,  Sarah E Lutz 5,  Ki-Wook Kim 3,  Akira Yoshii 5,  Nicolas Chevrier 2,  Makoto Inoue 4,  Teruyuki Sano 10
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, Chicago, IL, USA.
  • 2 Pritzker School of Molecular Engineering, University of Chicago, Chicago, USA.
  • 3 Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago College of Medicine, Chicago, IL, USA.
  • 4 Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 5 Department of Anatomy and Cell Biology, University of Illinois at Chicago College of Medicine, Chicago, IL, USA.
  • 6 Department of Pathology, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt.
  • 7 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 8 Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, IL, USA.
  • 9 Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
  • 10 Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, Chicago, IL, USA. tsano1@uic.edu.
PMID: 40533562 DOI: 10.1038/s41586-025-09120-w
Abstract

The microbiota has been recognized as a critical contributor to various diseases1, with multiple reports of changes in the composition of the gut microbiome in contexts such as inflammatory bowel disease2,3 and neurodegenerative diseases4. These microbial shifts can exert systemic effects by altering the release of specific metabolites into the bloodstream5,6, and the gastrointestinal microbiota has also been reported to exhibit immunomodulatory activity through the activation of innate and adaptive immunity7,8. However, it remains unclear how the microbiota contributes to inflammation in the central nervous system (CNS), where these Microorganisms are typically absent. Here we report that T cells that recognize gut-colonizing segmented filamentous bacteria can induce inflammation in the mouse intestine and CNS in the absence of functional regulatory T cells. Gut commensal-specific CD4 T cells (Tcomm cells) that are dysregulated in the inflamed gut can become licensed to infiltrate into the CNS regardless of their antigen specificity and have the potential to be re-stimulated by host protein-derived antigens in the CNS via molecular mimicry, whereupon they produce high levels of GM-CSF, IFNγ and IL-17A, triggering neurological damage. These infiltrated Tcomm cells initiate CNS inflammation by activating microglia through their IL-23R-dependent encephalitogenic programme and their IL-23R-independent GM-CSF production. Together, our findings reveal potential mechanisms whereby perturbation of Tcomm cells can contribute to extraintestinal inflammation.

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