Tompkins Stephen Mark, Padilla Josette, Dal Canto Mauro C, Ting Jenny P-Y, Van Kaer Luc, Miller Stephen D
Department of Microbiology-Immunology and Pathology, Northwestern University Medical School, Chicago, IL 60611, USA.
J Immunol. 2002 Apr 15;168(8):4173-83. doi: 10.4049/jimmunol.168.8.4173.
We demonstrate the absolute requirement for a functioning class II-restricted Ag processing pathway in the CNS for the initiation of experimental autoimmune encephalomyelitis (EAE). C57BL/6 (B6) mice deficient for the class II transactivator, which have defects in MHC class II, invariant chain (Ii), and H-2M (DM) expression, are resistant to initiation of myelin oligodendrocyte protein (MOG) peptide, MOG(35-55)-specific EAE by both priming and adoptive transfer of encephalitogenic T cells. However, class II transactivator-deficient mice can prime a suboptimal myelin-specific CD4(+) Th1 response. Further, B6 mice individually deficient for Ii and DM are also resistant to initiation of both active and adoptive EAE. Although both Ii-deficient and DM-deficient APCs can present MOG peptide to CD4(+) T cells, neither is capable of processing and presenting the encephalitogenic peptide of intact MOG protein. This phenotype is not Ag-specific, as DM- and Ii-deficient mice are also resistant to initiation of EAE by proteolipid protein peptide PLP(178-191). Remarkably, DM-deficient mice can prime a potent peripheral Th1 response to MOG(35-55), comparable to the response seen in wild-type mice, yet maintain resistance to EAE initiation. Most striking is the demonstration that T cells from MOG(35-55)-primed DM knockout mice can adoptively transfer EAE to wild-type, but not DM-deficient, mice. Together, these data demonstrate that the inability to process antigenic peptide from intact myelin protein results in resistance to EAE and that de novo processing and presentation of myelin Ags in the CNS is absolutely required for the initiation of autoimmune demyelinating disease.
我们证明，在中枢神经系统中，启动实验性自身免疫性脑脊髓炎（EAE）绝对需要一条功能正常的II类限制性抗原加工途径。缺乏II类反式激活因子的C57BL/6（B6）小鼠在MHC II类、恒定链（Ii）和H-2M（DM）表达方面存在缺陷，通过致敏性T细胞的启动和过继转移，对髓鞘少突胶质细胞糖蛋白（MOG）肽、MOG(35-55)特异性EAE的启动具有抗性。然而，缺乏II类反式激活因子的小鼠能够启动次优的髓鞘特异性CD4(+) Th1反应。此外，单独缺乏Ii和DM的B6小鼠对主动和过继性EAE的启动也具有抗性。尽管缺乏Ii和缺乏DM的抗原呈递细胞（APC）都能将MOG肽呈递给CD4(+) T细胞，但两者都无法加工和呈递完整MOG蛋白的致脑炎肽。这种表型不是抗原特异性的，因为缺乏DM和缺乏Ii的小鼠对由脂蛋白蛋白肽PLP(178-191)引发的EAE也具有抗性。值得注意的是，缺乏DM的小鼠能够启动对MOG(35-55)的强效外周Th1反应，与野生型小鼠中观察到的反应相当，但对EAE的启动仍保持抗性。最引人注目的是，来自经MOG(35-55)致敏的DM基因敲除小鼠的T细胞能够将EAE过继转移给野生型小鼠，但不能转移给缺乏DM的小鼠。总之，这些数据表明，无法从完整的髓鞘蛋白加工抗原肽会导致对EAE的抗性，并且中枢神经系统中髓鞘抗原的从头加工和呈递是启动自身免疫性脱髓鞘疾病所绝对必需的。
