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

Zachary White, Ivan Cabrera, Linghan Mei, Margarette Clevenger, Andrea Ochoa-Raya, Isabel Kapustka, Joseph R. Dominguez, Jinyan Zhou, Kevin P. Koster, Shehata Anwar, Qianxun Wang, Charles Ng, Shoko Sagoshi, Takashi Matsuo, Dulari Jayawardena, Seung Hyeon Kim, Takahiro Kageyama, Benjamin J. Mitchell, Dante Rivera, Pradeep K. Dudeja, Sarah E. Lutz, Ki-Wook Kim, Akira Yoshii, Nicolas Chevrier, Makoto Inoue and Teruyuki Sano ()
Additional contact information
Zachary White: University of Illinois at Chicago College of Medicine
Ivan Cabrera: University of Illinois at Chicago College of Medicine
Linghan Mei: University of Chicago
Margarette Clevenger: University of Chicago
Andrea Ochoa-Raya: University of Illinois at Chicago College of Medicine
Isabel Kapustka: University of Illinois at Chicago College of Medicine
Joseph R. Dominguez: University of Illinois at Chicago College of Medicine
Jinyan Zhou: University of Illinois at Urbana-Champaign
Kevin P. Koster: University of Illinois at Chicago College of Medicine
Shehata Anwar: University of Illinois at Urbana-Champaign
Qianxun Wang: University of Illinois at Chicago College of Medicine
Charles Ng: Memorial Sloan Kettering Cancer Center
Shoko Sagoshi: University of Illinois at Chicago College of Medicine
Takashi Matsuo: University of Illinois at Chicago College of Medicine
Dulari Jayawardena: University of Illinois at Chicago College of Medicine
Seung Hyeon Kim: University of Illinois at Chicago College of Medicine
Takahiro Kageyama: University of Illinois at Chicago College of Medicine
Benjamin J. Mitchell: University of Illinois at Chicago College of Medicine
Dante Rivera: University of Illinois at Chicago College of Medicine
Pradeep K. Dudeja: University of Illinois at Chicago College of Medicine
Sarah E. Lutz: University of Illinois at Chicago College of Medicine
Ki-Wook Kim: University of Illinois at Chicago College of Medicine
Akira Yoshii: University of Illinois at Chicago College of Medicine
Nicolas Chevrier: University of Chicago
Makoto Inoue: University of Illinois at Urbana-Champaign
Teruyuki Sano: University of Illinois at Chicago College of Medicine

Nature, 2025, vol. 643, issue 8071, 509-518

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09120-w

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