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

• 成果类型: Article
• 署名作者: White, Zachary; Cabrera, Ivan; Mei, Linghan; Clevenger, Margarette; Ochoa-Raya, Andrea; Kapustka, Isabel; Dominguez, Joseph R.; Zhou, Jinyan; Koster, Kevin P.; Anwar, Shehata; Wang, Qianxun; Ng, Charles; Sagoshi, Shoko; Matsuo, Takashi; Jayawardena, Dulari; Kim, Seung Hyeon; Kageyama, Takahiro; Mitchell, Benjamin J.; Rivera, Dante; Dudeja, Pradeep K.; Lutz, Sarah E.; Kim, Ki-Wook; Yoshii, Akira; Chevrier, Nicolas; Inoue, Makoto; Sano, Teruyuki
• 署名单位: University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; University of Chicago; University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; University of Illinois System; University of Illinois Urbana-Champaign; University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; Egyptian Knowledge Bank (EKB); Beni Suef University; Memorial Sloan Kettering Cancer Center; University of Illinois System; University of Illinois Chicago; University of Illinois Chicago Hospital; US Department of Veterans Affairs; Veterans Health Administration (VHA); Jesse Brown VA Medical Center
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09120-w
• 发表日期: 2025-07-10
• 页码: 509-+
• 关键词: segmented filamentous bacteria; intestinal inflammation; t(h)17 cells; mice; th17; autoimmunity; induce; identification; homeostasis; activation

摘要

The microbiota has been recognized as a critical contributor to various diseases(1), with multiple reports of changes in the composition of the gut microbiome in contexts such as inflammatory bowel disease(2,3) and neurodegenerative diseases(4). These microbial shifts can exert systemic effects by altering the release of specific metabolites into the bloodstream(5,6), and the gastrointestinal microbiota has also been reported to exhibit immunomodulatory activity through the activation of innate and adaptive immunity(7,8). 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, IFN gamma and IL-17A, triggering neurological damage. These infiltrated T-comm 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 T-comm cells can contribute to extraintestinal inflammation.