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

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 ( = 44), primary progressive MS (PPMS) patients ( = 25), or healthy controls ( = 42), but Eomes Th cells were significantly increased in SPMS ( = 105, < 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 ( < 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.