CD44 reciprocally regulates the differentiation of encephalitogenic Th1/Th17 and Th2/Treg cells through epigenetic modulation involving DNA methylation of cytokine gene promoters thereby controlling the development of experimental autoimmune encephalomyelitis

摘要

CD44 is expressed by variety of cells, including glial and T cells. Furthermore, in the demyelinating lesions of multiple sclerosis (MS), CD44 expression is chronically elevated. In this study, we demonstrate that targeted deletion of CD44 attenuated MOG peptide-induced experimental autoimmune encephalitomyelitis (EAE) through novel regulatory mechanisms affecting Th differentiation. Specifically, by developing chimeras and using adoptive transfer experiments, we noted that CD44 deficiency on CD4⁺ T cells but not other cells, conferred protection against EAE induction. CD44 expression played a crucial role in Th differentiation, in as much as, deletion of CD44 inhibited Th1/Th17 differentiation while simultaneously enhancing Th2/Treg differentiation. In contrast, expression of CD44 promoted Th1/Th17 differentiation. When osteopontin (OPN) and hyaluronic acid (HA), the two major ligands of CD44 were tested for their role in Th differentiation, OPN but not HA promoted Th1/Th17 differentiation. Furthermore, activation of CD44+ encephalitogenic T cells with MOG peptide led to demethylation at the ifnγ/il17a promoter region while displaying hypermethylation at the il4/foxp3 gene promoter. Interestingly, similar activation of CD44-deficient encephalitogenic T cells led to increased hypermethylation of ifnγ/il17a gene and marked demethylation of il4/foxp3 gene promoter. Together, these data suggested that signaling through CD44, in encephalitogenic T cells, plays a crucial role in the differentiation of T helper cells through epigenetic regulation, specifically DNA methylation of Th1/Th17 and Th2 cytokine genes. The current study also suggests that molecular targeting of CD44 receptor to promote a switch from Th1/Th17 to Th2/Treg differentiation may provide a novel treatment modality against EAE.