Journal Article

Protective effect of TCR-mediated MAIT cell activation during experimental autoimmune encephalomyelitis

Walkenhorst, Mark, Winkler, Iris, Sonner, Jana K., Lantz, Olivier, Salinas, Gabriela, Bauer, Simone, Vieira, Vanessa, Friese, Manuel A., Willing, Anne, Winschel, Ingo, Raich, Lukas, Woo, Marcel S., Meurs, Nina, Unger, Lisa, Engler, Jan Broder

2024

Overview

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-bet + RORγt + ) 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. Mucosal-associated invariant T (MAIT) cells mediate protection from pathogens, but their role in autoimmunity is unclear. Here the authors show that, in a mouse experimental autoimmune encephalomyelitis model, MAIT cells accumulate in the inflamed central nervous system and serve protective functions when activated via their T cell receptor.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 14 / 49/91 / 631/250/1619/554 / 631/250/2152/1566/1618 / 631/250/371 / 631/250/38 / 64/60 / Amphiregulin / Animals / Antigens / Autoimmunity / Cell activation / Central nervous system / Central Nervous System - immunology / Cytokines - immunology / Cytokines - metabolism / Encephalomyelitis / Encephalomyelitis, Autoimmune, Experimental - immunology / Experimental allergic encephalomyelitis / Female / Histocompatibility Antigens Class I - immunology / Histocompatibility Antigens Class I - metabolism / Humanities and Social Sciences / Immune system / Inflammation / Invariants / Lymphocyte Activation - immunology / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Metabolites / Mice / Mice, Inbred C57BL / Minor Histocompatibility Antigens - genetics / Minor Histocompatibility Antigens - immunology / Minor Histocompatibility Antigens - metabolism / Mucosa / Mucosal-Associated Invariant T Cells - immunology / multidisciplinary / Multiple sclerosis / Multiple Sclerosis - immunology / Nervous system / Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism / Pathogenesis / Receptors / Receptors, Antigen, T-Cell - immunology / Receptors, Antigen, T-Cell - metabolism / Ribitol - analogs & derivatives / Ribitol - immunology / Riboflavin / Science / Science (multidisciplinary) / T cell receptors / Transcriptomes / Uracil - analogs & derivatives / Uracil - pharmacology / Yeast