Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA.
J Immunol. 2011 Jun 15;186(12):6955-64. doi: 10.4049/jimmunol.1004043. Epub 2011 May 6.
CD44 is expressed by a variety of cells, including glial and T cells. Furthermore, in the demyelinating lesions of multiple sclerosis, CD44 expression is chronically elevated. In this study, we demonstrate that targeted deletion of CD44 attenuated myelin oligodendrocyte glycoprotein 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, inasmuch as deletion of CD44 inhibited Th1/Th17 differentiation while simultaneously enhancing Th2/regulatory T cell differentiation. In contrast, expression of CD44 promoted Th1/Th17 differentiation. When osteopontin and hyaluronic acid, the two major ligands of CD44, were tested for their role in Th differentiation, osteopontin, but not hyaluronic acid, promoted Th1/Th17 differentiation. Furthermore, activation of CD44(+) encephalitogenic T cells with myelin oligodendrocyte glycoprotein 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 Th 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/regulatory T cell differentiation may provide a novel treatment modality against EAE.
CD44 表达于多种细胞，包括神经胶质细胞和 T 细胞。此外，在多发性硬化症的脱髓鞘病变中，CD44 的表达呈慢性升高。在这项研究中，我们证明通过影响 Th 分化的新型调节机制，靶向敲除 CD44 可减弱髓鞘少突胶质细胞糖蛋白肽诱导的实验性自身免疫性脑脊髓炎 (EAE)。具体而言，通过建立嵌合体并使用过继转移实验，我们注意到 CD44 缺陷仅发生在 CD4(+) T 细胞，而不是其他细胞，可预防 EAE 的诱导。CD44 的表达在 Th 分化中起着至关重要的作用，因为敲除 CD44 抑制 Th1/Th17 分化，同时增强 Th2/调节性 T 细胞分化。相反，CD44 的表达促进 Th1/Th17 分化。当测试 CD44 的两个主要配体——骨桥蛋白和透明质酸在 Th 分化中的作用时，发现骨桥蛋白而不是透明质酸促进 Th1/Th17 分化。此外，用髓鞘少突胶质细胞糖蛋白肽激活 CD44(+)致脑炎 T 细胞导致 ifnγ/il17a 启动子区域去甲基化，同时在 il4/foxp3 基因启动子上显示高度甲基化。有趣的是，类似地激活 CD44 缺陷致脑炎 T 细胞导致 ifnγ/il17a 基因的高度甲基化增加和 il4/foxp3 基因启动子的显著去甲基化。总之，这些数据表明，在致脑炎 T 细胞中，通过 CD44 信号传导在通过表观遗传调控，特别是 Th1/Th17 和 Th2 细胞因子基因的 DNA 甲基化中，在 Th 细胞分化中起着至关重要的作用。本研究还表明，针对 CD44 受体的分子靶向以促进从 Th1/Th17 向 Th2/调节性 T 细胞分化的转变可能为 EAE 提供一种新的治疗方法。
