Deciphering the role of CNS-infiltrating MAIT cells in autoimmune CNS inflammation
Final Report Abstract
MAIT cells are a special type of immune cell found mostly in the gut and liver, but at lower numbers also in the blood and other tissues in humans and mice. They detect vitamin B2-related molecules originating for example from bacteria of the gut microbiome and respond to infections or inflammation. In multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), fewer MAIT cells are found in the blood and they appear in the inflammatory brain lesions. They are able to produce pro-inflammatory molecules such as IL-17, a molecule linked to MS, but more recent studies suggest that MAIT cells can also serve protective function in autoimmunity. This project aimed to better understand how MAIT cells behave in MS by use of its mouse model experimental autoimmune encephalomyelitis (EAE). Here, we found that activated MAIT cells move into the CNS and produce inflammatory molecules like IL-17 and IFNγ. But also, molecules related to tissue repair function were upregulated by MAIT cells in the CNS in EAE. Their protective potential even outweighed their pro-inflammatory function, as mice lacking them had worse disease outcomes. Furthermore, when MAIT cells were stimulated by treating mice with a MAIT-specific antigen (5-OP-RU), their protective effects increased, reducing disease severity in EAE. Vice versa, blocking their activation via their T cell receptor (TCR) worsened the disease. One key protective molecule MAIT cells produce is amphiregulin (AREG), which was especially high in MAIT cells in the CNS and could even be increased by 5-OP-RU treatment. These findings suggest that boosting MAIT cell activity by 5-OP-RU treatment or by influencing the gut microbiome could potentially reduce inflammation and support tissue repair in MS. However, further investigation of the precise mechanism of action and of the translatability of our findings to humans are needed.
Publications
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Mucosal-associated invariant T cells contribute to suppression of inflammatory myeloid cells in immune-mediated kidney disease. Nature Communications, 14(1).
Gnirck, Ann-Christin; Philipp, Marie-Sophie; Waterhölter, Alex; Wunderlich, Malte; Shaikh, Nikhat; Adamiak, Virginia; Henneken, Lena; Kautz, Tobias; Xiong, Tingting; Klaus, Daniela; Tomczyk, Pascal; Al-Bahra, Mohamad M.; Menche, Dirk; Walkenhorst, Mark; Lantz, Olivier; Willing, Anne; Friese, Manuel A.; Huber, Tobias B.; Krebs, Christian F. ... & Turner, Jan-Eric
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Protective effect of TCR-mediated MAIT cell activation during experimental autoimmune encephalomyelitis. Nature Communications, 15(1).
Walkenhorst, Mark; Sonner, Jana K.; Meurs, Nina; Engler, Jan Broder; Bauer, Simone; Winschel, Ingo; Woo, Marcel S.; Raich, Lukas; Winkler, Iris; Vieira, Vanessa; Unger, Lisa; Salinas, Gabriela; Lantz, Olivier; Friese, Manuel A. & Willing, Anne
