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

Abstract

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.

CCR6 and CXCR6 Identify the Th17 Cells With Cytotoxicity in Experimental Autoimmune Encephalomyelitis

“…Interestingly, we found that CD4 cells in the spinal cord were cytotoxic by highly expressing Granzyme(s) and cognate serine protease inhibitor Serpin(s) along with IFNg and GM-CSF (Figure 1F). Indeed, this finding matches with the human MS study that CD4 cells from human secondary progressive MS autopsy brain samples are cytotoxic by co-expression of Eomes and Granzyme-B (19).…”

Contact-Dependent Granzyme B-Mediated Cytotoxicity of Th17-Polarized Cells Toward Human Oligodendrocytes

“…Interestingly, we observed that the expression (raw counts) of CD28 mRNA was generally low, especially in cells with high expression of GZMB in Th17-polarized cells in coculture with OLs by single-cell RNA sequencing ( Supplementary Figure 9B ). Granzyme B levels are elevated in the CSF of MS patients ( 42 ) and CD4 + T cells from MS patients secrete more granzyme B than healthy controls in the relapsing–remitting ( 85 ) and progressive forms ( 86 ). In addition, pro-inflammatory CD4 + T cells secreting granzyme B can disrupt the blood–brain barrier ( 87 ) and cause glial fibrillary acid protein fragmentation in human primary astrocytes in vitro ( 22 ).…”

Dual roles of granzyme B

“…73 Moreover, the abundance of GZMB-expressing Eomes + T helper cells increased in the pathogenesis of secondary progressive multiple sclerosis. 74 These studies demonstrate the potential utility of GZMB and GZMB + cells as a marker for the identification, diagnosis and treatment of a variety of diseases.…”