Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
NGS-Integrative Genomics Core Unit, Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
Nat Commun. 2024 Oct 28;15(1):9287. doi: 10.1038/s41467-024-53657-9.
Mucosal-associated invariant T (MAIT) cells express semi-invariant T cell receptors (TCR) for recognizing bacterial and yeast antigens derived from riboflavin metabolites presented on the non-polymorphic MHC class I-related protein 1 (MR1). Neuroinflammation in multiple sclerosis (MS) is likely initiated by autoreactive T cells and perpetuated by infiltration of additional immune cells, but the precise role of MAIT cells in MS pathogenesis remains unknown. Here, we use experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, and find an accumulation of MAIT cells in the inflamed central nervous system (CNS) enriched for MAIT17 (RORγt) and MAIT1/17 (T-betRORγt) subsets with inflammatory and protective features. Results from transcriptome profiling and Nur77GFP reporter mice show that these CNS MAIT cells are activated via cytokines and TCR. Blocking TCR activation with an anti-MR1 antibody exacerbates EAE, whereas enhancing TCR activation with the cognate antigen, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil, ameliorates EAE severity, potentially via the induction of amphiregulin (AREG). In summary, our findings suggest that TCR-mediated MAIT cell activation is protective in CNS inflammation, likely involving an induction of AREG.
黏膜相关不变 T（MAIT）细胞表达半不变 T 细胞受体（TCR），用于识别来自核黄素代谢物的细菌和酵母抗原，这些抗原在非多态性 MHC 类相关蛋白 1（MR1）上呈递。多发性硬化症（MS）中的神经炎症可能由自身反应性 T 细胞引发，并通过其他免疫细胞的浸润而持续存在，但 MAIT 细胞在 MS 发病机制中的确切作用仍不清楚。在这里，我们使用实验性自身免疫性脑脊髓炎（EAE），即 MS 的小鼠模型，发现 MAIT 细胞在炎症性中枢神经系统（CNS）中积累，这些细胞富含 MAIT17（RORγt）和 MAIT1/17（T-betRORγt）亚群，具有炎症和保护特征。转录组谱分析和 Nur77GFP 报告小鼠的结果表明，这些 CNS MAIT 细胞通过细胞因子和 TCR 被激活。用抗 MR1 抗体阻断 TCR 激活会加重 EAE，而用同源抗原 5-（2-氧代丙基二亚氨基）-6-D-核糖尿嘧啶胺增强 TCR 激活可改善 EAE 严重程度，可能通过诱导 Amphiregulin（AREG）。总之，我们的研究结果表明，TCR 介导的 MAIT 细胞激活在 CNS 炎症中具有保护作用，可能涉及 AREG 的诱导。
