Role of MHC class II expressing CD4+ T cells in proteolipid protein91-110-induced EAE in HLA-DR3 transgenic mice
Role of MHC class II expressing CD4+ T cells in proteolipid protein91-110-induced EAE in HLA-DR3 transgenic mice
复制标题
DOI：
10.1002/eji.200636217
复制
发表时间：
2006-12-01
影响因子：
5.4
通讯作者：
David, Chella
中科院分区：
文献类型：
--
作者：
Mangalam, Ashutosh;Rodriguez, Moses;David, Chella
MHC II类分子通过选择胸腺中的CD4(+) T细胞库和外周抗原呈递，在控制适应性免疫应答中发挥核心作用。多发性硬化症、类风湿性关节炎和IDDM等自身免疫性疾病的遗传易感性与特定的MHC II类等位基因有关。HLA转基因小鼠的出现帮助我们破译了特定的HLA DR和DQ II类分子在人类自身免疫性疾病中的作用。在小鼠中，II类的表达仅限于专业抗原呈递细胞（APC）。然而，与小鼠的T细胞不同，在人类中，II类也在T细胞上表达。我们开发了新的人源化HLA II类转基因小鼠，不仅在APC上表达II类分子，而且在CD4(+) T细胞亚群上表达II类分子。II类在CD4(+) T细胞上的表达是可诱导的，并且II类+ CD4(+) T细胞在没有APC的情况下也能提呈抗原。此外，我们使用EAE（一种成熟的MS动物模型）测试了这些II+ CD4(+) T细胞的功能意义。DR3。AEo转基因小鼠易受蛋白脂蛋白（91-110）诱导的EAE的影响，并表现出人类MS患者常见的CNS病理，伴有广泛的炎症和脱髓鞘，提示II类+ CD4(+) T细胞在发病机制中起作用。
MHC class II molecules play a central role in the control of adaptive immune responses through selection of the CD4(+) T cell repertoire in the thymus and antigen presentation in the periphery. Inherited susceptibility to autoimmune disorders such as multiple sclerosis, rheumatoid arthritis and IDDM are associated with particular MHC class II alleles. Advent of HLA transgenic mice has helped us in deciphering the role of particular HLA DR and DQ class II molecules in human autoimmune diseases. In mice, the expression of class II is restricted to professional antigen-presenting cells (APC). However, in humans, class II is also expressed on T cells, unlike murine T cells. We have developed new humanized HLA class II transgenic mice expressing class II molecules not only on APC but also on a subset of CD4(+) T cells. The expression of class II on CD4(+) T cells is inducible, and class II+ CD4(+) T cells can present antigen in the absence of APC. Further, using EAE, a well-established animal model of MS, we tested the functional significance of these class II+ CD4(+) T cells. DR3.AEo transgenic mice were susceptible to proteolipid protein(91-110)-induced EAE and showed CNS pathology accompanied by widespread inflammation and demyelination seen in human MS patients, suggesting a role for class II+ CD4(+) T cells in the pathogenesis.