Involvement of cytotoxic Eomes-expressing CD4 + T cells in secondary progressive multiple sclerosis

Ben J E Raveney, Wakiro Sato, Daiki Takewaki, Chenyang Zhang, Tomomi Kanazawa, Youwei Lin, Tomoko Okamoto, Manabu Araki, Yukio Kimura, Noriko Sato, Terunori Sano, Yuko Saito, Shinji Oki, Takashi Yamamura
Proceedings of the National Academy of Sciences of the United States of America 2021 March 16, 118 (11)
Multiple sclerosis (MS), a putative autoimmune disease of the central nervous system (CNS), commonly presents as relapsing-remitting MS (RRMS), characterized by recurrent episodes of peripheral disabling symptoms resulting from inflammatory CNS damage. Many RRMS patients transition to a chronic disease course with progressive neurological dysfunctions (secondary progressive MS, SPMS), with the progression rate varying between patients and over time. SPMS pathogenesis is now linked to immune-cell-mediated processes, although the mechanisms driving SPMS transition and progression remain elusive, and SPMS lacks biomarkers and effective treatments. We report the crucial involvement of cytotoxic CD4+ T cells expressing Eomes (Eomes+ Th cells) in SPMS pathogenesis-a Th cell subset previously identified in a mouse model of late/chronic autoimmune CNS inflammation. Few Eomes+ Th cells circulate in RRMS patient peripheral blood ( n = 44), primary progressive MS (PPMS) patients ( n = 25), or healthy controls ( n = 42), but Eomes+ Th cells were significantly increased in SPMS ( n = 105, P < 0.0001). Strikingly, lymphocytes isolated from SPMS autopsy brain samples revealed CD4+ T cells infiltrating CNS that coexpressed Eomes and the cytotoxic molecule granzyme B. In particular, the Eomes+ Th cell levels were increased in SPMS patients in progressive disease phases versus SPMS patients without current disability increases ( P < 0.0001). Moreover, Eomes level acted as a biomarker to predict SPMS patients at risk of disease worsening with over 80% accuracy (ROC-AUC = 0.8276). Overall, our results indicate that granzyme B-expressing Eomes+ T helper cells are involved in the pathogenesis of SPMS, with significant implications for SPMS biomarkers and therapeutic targets.

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