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
Department of Microbiology and Immunology, University of Illinois at Chicago College of Medicine, Chicago, IL, USA.
Pritzker School of Molecular Engineering, University of Chicago, Chicago, USA.
Nature. 2025 Jun 18. doi: 10.1038/s41586-025-09120-w.
The microbiota has been recognized as a critical contributor to various diseases, with multiple reports of changes in the composition of the gut microbiome in contexts such as inflammatory bowel disease and neurodegenerative diseases. These microbial shifts can exert systemic effects by altering the release of specific metabolites into the bloodstream, and the gastrointestinal microbiota has also been reported to exhibit immunomodulatory activity through the activation of innate and adaptive immunity. 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 (T 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 T 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 cells can contribute to extraintestinal inflammation.
微生物群已被认为是多种疾病的关键促成因素，有多项报告指出，在炎症性肠病和神经退行性疾病等情况下，肠道微生物组的组成会发生变化。这些微生物变化可通过改变特定代谢产物向血液中的释放而产生全身影响，并且据报道，胃肠道微生物群还可通过激活先天性和适应性免疫来表现出免疫调节活性。然而，目前尚不清楚微生物群如何导致中枢神经系统（CNS）发生炎症，因为在中枢神经系统中通常不存在这些微生物。在此，我们报告称，在缺乏功能性调节性T细胞的情况下，识别定居于肠道的分节丝状菌的T细胞可在小鼠肠道和中枢神经系统中诱导炎症。在发炎肠道中失调的肠道共生特异性CD4 T细胞（T细胞）无论其抗原特异性如何，都可获得许可浸润到中枢神经系统中，并有可能通过分子模拟被中枢神经系统中宿主蛋白衍生的抗原重新刺激，随后它们会产生高水平的粒细胞-巨噬细胞集落刺激因子（GM-CSF）、干扰素γ（IFNγ）和白细胞介素-17A（IL-17A），从而引发神经损伤。这些浸润的T细胞通过其依赖白细胞介素-23受体（IL-23R）的致脑炎程序及其不依赖IL-23R的GM-CSF产生来激活小胶质细胞，从而引发中枢神经系统炎症。总之，我们的研究结果揭示了T细胞扰动可能导致肠外炎症的潜在机制。
