The role of the MHC class II transactivator in class II expression and antigen presentation by astrocytes and in susceptibility to central nervous system autoimmune disease
The role of the MHC class II transactivator in class II expression and antigen presentation by astrocytes and in susceptibility to central nervous system autoimmune disease
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DOI：
10.4049/jimmunol.169.12.6720
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发表时间：
2002-12-15
影响因子：
4.4
通讯作者：
Zamvil, SS
中科院分区：
文献类型：
--
作者：
Stüve, O;Youssef, S;Zamvil, SS
研究了MHC II类反式激活因子（CIITA）在星形胶质细胞抗原呈递和实验性自身免疫性脑脊髓炎（EAE）易感性中的作用，使用CIITA缺陷小鼠和新创建的转基因小鼠，其使用胶质细胞酸性蛋白启动子靶向星形胶质细胞中的CIITA表达。CIITA是星形胶质细胞II类蛋白表达所必需的。与II类缺陷小鼠一样，CIITA缺陷小鼠通过用CNS自身抗原免疫对EAE具有抗性，尽管来自免疫的CIITA缺陷小鼠的T细胞增殖并分泌Th 1细胞因子，但II类缺陷小鼠没有。CIITA缺陷的脾APC向纯化的野生型致脑炎性CD 4（+）T细胞呈递致脑炎性肽，表明CIITA非依赖性机制可用于淋巴组织中II类限制性Ag的呈递。CIITA缺陷型小鼠通过过继转移致脑炎II类限制性CD 4（+）Th 1细胞也对EAE具有抗性，表明CIITA依赖性II类表达是CNS Ag呈递所必需的。尽管组成CIITA驱动的II类表达星形胶质细胞在体内，胶质细胞酸性蛋白-CIITA转基因小鼠并不比对照组更容易EAE。CIITA转染的星形胶质细胞呈现肽Ag，但与IFN-γ激活的星形胶质细胞相反，它们不能处理和呈现天然Ag。CIITA转染的星形胶质细胞在没有IFN-γ激活的情况下不表达组织蛋白酶S，表明CIITA不调节星形胶质细胞加工Ag所需的其他元素。虽然我们的研究结果表明，CIITA指导的II类表达所需的EAE诱导，CIITA指导的星形胶质细胞的II类表达似乎并没有增加EAE的易感性。这些结果不支持星形胶质细胞作为APC在EAE诱导阶段用于II类限制性Ag呈递的作用。
The role of the MHC class II transactivator (CIITA) in Ag presentation by astrocytes and susceptibility to experimental autoimmune encephalomyelitis (EAE) was examined using CIITA-deficient mice and newly created transgenic mice that used the glial fibrillary acidic protein promoter to target CIITA expression in astrocytes. CIITA was required for class II expression on astrocytes. Like class II-deficient mice, CIITA-deficient mice were resistant to EAE by immunization with CNS autoantigen, although T cells from immunized CIITA-deficient, but not class II-deficient, mice proliferated and secreted Th1 cytokines. CIITA-deficient splenic APC presented encephalitogenic peptide to purified wild-type encephalitogenic CD4(+) T cells, indicating that CIITA-independent mechanisms can be used for class II-restrieted Ag presentation in lymphoid tissue. CIITA-deficient mice were also resistant to EAE by adoptive transfer of encephalitogenic class II-restricted CD4(+) Th1 cells, indicating that CIITA-dependent class II expression was required for CNS Ag presentation. Despite constitutive CIITA-driven class II expression on astrocytes in vivo, glial fibrillary acidic protein-CIITA transgenic mice were no more susceptible to EAE than controls. CIITA-transfected astrocytes presented peptide Ag, but in contrast to IFN-gamma-activated astrocytes, they could not process and present native Ag. CIITA-transfected astrocytes did not express cathepsin S without IFN-gamma activation, indicating that CIITA does not regulate other elements that may be required for Ag processing by astrocytes. Although our results demonstrate that CIITA-directed class II expression is required for EAE induction, CIITA-directed class II expression by astrocytes does not appear to increase EAE susceptibility. These results do not support the role of astrocytes as APC for class II-restricted Ag presentation during the induction phase of EAE.