B Cells Drive MHC Class I-Restricted CD4 T Cells to Induce Spontaneous Central Nervous System Autoimmunity.
B Cells Drive MHC Class I-Restricted CD4 T Cells to Induce Spontaneous Central Nervous System Autoimmunity.
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DOI：
10.4049/jimmunol.2200494
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发表时间：
2022-11-15
期刊：
影响因子：
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通讯作者：
Goverman JM
中科院分区：
文献类型：
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作者：
Matter AL;Liggitt D;Goverman JM
多发性硬化症(MS)是一种炎症性、脱髓鞘的中枢神经系统疾病，被认为是由中枢神经系统自身抗原特异性的CD4T细胞介导的。CD8T细胞也与多发性硬化症有关，但其功能尚不清楚。多发性硬化症的病变是异质性的，可能反映了不同类型淋巴细胞的贡献差异。了解具有不同效应功能的淋巴细胞如何对多发性硬化症做出贡献，对于开发有效的治疗方法至关重要。我们利用实验性自身免疫性脑脊髓炎(EAE)的小鼠模型，研究了表达针对髓鞘碱性蛋白(MBP)的MHC-I类限制性转基因TCR的T细胞在中枢神经系统自身免疫中的作用。病毒感染以干扰素-γ和穿孔素依赖的方式触发TcR转基因细胞毒性CD8T细胞启动急性EAE。出乎意料的是，在干扰素-γ缺乏加速的TCR转基因小鼠中，出现了自发的中枢神经系统自身免疫。自发性疾病与CD4T细胞有关，CD4T细胞通过内源性TCR重排发育，但保留MHC I类限制性MBP表位的特异性。CD4T细胞产生不含其他炎性细胞因子的肿瘤坏死因子-α，引起的病变与MS活动性病变有显著的相似性。令人惊讶的是，B细胞是交叉呈现MBP的主要细胞类型，它们的耗尽阻止了疾病的进展。这项工作提供了一种新的自发CNS自身免疫模型，与MS有独特的相似之处，它是由具有不同效应表型的T细胞介导的。
Multiple sclerosis (MS) is an inflammatory, demyelinating CNS disease believed to be mediated by CD4 T cells specific for CNS self-antigens. CD8 T cells are also implicated in MS but their function is not well understood. MS lesions are heterogeneous and may reflect variation in the contribution of different types of lymphocytes. Understanding how lymphocytes with different effector functions contribute to MS is essential to develop effective therapies. We investigated how T cells expressing an MHC class I-restricted transgenic TCR specific for myelin basic protein (MBP) contribute to CNS autoimmunity using the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Virus infection triggered cytotoxic TCR-transgenic CD8 T cells to initiate acute EAE in an IFN-γ- and perforin-dependent manner. Unexpectedly, spontaneous CNS autoimmunity developed in the TCR-transgenic mice that was accelerated by IFN-γ-deficiency. Spontaneous disease was associated with CD4 T cells that develop via endogenous TCR rearrangements but retain specificity for the MHC class I-restricted MBP epitope. The CD4 T cells produced TNF-α without other inflammatory cytokines and caused lesions with striking similarity to active MS lesions. Surprisingly, B cells were the predominant cell type that cross-presented MBP and their depletion halted disease progression. This work provides a new model of spontaneous CNS autoimmunity with unique similarities to MS that is mediated by T cells with a distinct effector phenotype.