CD44 Reciprocally regulates the differentiation of encephalitogenic Th1/Th17 and Th2/regulatory T cells through epigenetic modulation involving DNA methylation of cytokine gene promoters, thereby controlling the development of experimental autoimmune encephalomyelitis.
CD44 Reciprocally regulates the differentiation of encephalitogenic Th1/Th17 and Th2/regulatory T cells through epigenetic modulation involving DNA methylation of cytokine gene promoters, thereby controlling the development of experimental autoimmune encephalomyelitis.
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DOI：
10.4049/jimmunol.1004043
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发表时间：
2011-06-15
期刊：
影响因子：
--
通讯作者：
Nagarkatti M
中科院分区：
文献类型：
--
作者：
Guan H;Nagarkatti PS;Nagarkatti M
CD 44由多种细胞表达，包括神经胶质细胞和T细胞。此外，在多发性硬化（MS）的脱髓鞘病变中，CD 44表达长期升高。在这项研究中，我们表明，有针对性地删除CD 44衰减MOG肽诱导的实验性自身免疫性脑脊髓炎（EAE）通过新的调节机制影响Th分化。具体地说，通过开发嵌合体和使用过继转移实验，我们注意到CD 4 + T细胞而不是其他细胞上的CD 44缺陷赋予了针对EAE诱导的保护。CD 44表达在Th细胞分化中起重要作用，CD 44缺失抑制Th 1/Th 17分化，同时促进Th 2/Treg分化。相反，CD 44的表达促进Th 1/Th 17分化。当检测CD 44的两种主要配体骨桥蛋白（OPN）和透明质酸（HA）在Th分化中的作用时，OPN而不是HA促进Th 1/Th 17分化。此外，用MOG肽活化CD 44+致脑炎性T细胞导致ifnγ/il 17 a启动子区域的去甲基化，同时在il 4/foxp 3基因启动子处显示高甲基化。有趣的是，CD 44缺陷致脑炎T细胞的类似激活导致ifnγ/il 17 a基因的高甲基化增加和il 4/foxp 3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CD 44的信号传导通过表观遗传调节，特别是Th 1/Th 17和Th 2细胞因子基因的DNA甲基化，在辅助性T细胞的分化中发挥着至关重要的作用。目前的研究还表明，分子靶向CD 44受体，以促进从Th 1/Th 17到Th 2/Treg分化的转换，可能会提供一种新的治疗模式，对EAE。
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.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
DOI：
10.4049/jimmunol.0802325
发表时间：
2009-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Guan H;Nagarkatti PS;Nagarkatti M
通讯作者：
Nagarkatti M
影响因子：
9.9
作者：
Kasper, Lloyd H.;Shoemaker, Jennifer
通讯作者：
Shoemaker, Jennifer
影响因子：
5.5
作者：
Hegde, Venkatesh L.;Singh, Narendra P.;Nagarkatti, Mitzi
通讯作者：
Nagarkatti, Mitzi
影响因子：
5.4
作者：
Chen, Mei-Ling;Yan, Bo-Shiun;Kozoriz, Deneen;Weiner, Howard L.
通讯作者：
Weiner, Howard L.