Th40 cells (CD4+CD40+ Tcells) drive a more severe form of Experimental Autoimmune Encephalomyelitis than conventional CD4 T cells

CD40-CD154 interaction is critically involved in autoimmune diseases, and CD4 T cells play a dominant role in the Experimental Autoimmune Encephalomyelitis (EAE) model of Multiple Sclerosis (MS). CD4 T cells expressing CD40 (Th40) are pathogenic in type I diabetes but have not been evaluated in EAE. We demonstrate here that Th40 cells drive a rapid, more severe EAE disease course than conventional CD4 T cells. Adoptively transferred Th40 cells are present in lesions in the CNS and are associated with wide spread demyelination. Primary Th40 cells from EAE-induced donors adoptively transfer EAE without further in-vitro expansion and without requiring the administration of the EAE induction regimen to the recipient animals. This has not been accomplished with primary, non-TCR-transgenic donor cells previously. If co-injection of Th40 donor cells with Freund’s adjuvant (CFA) in the recipient animals is done, the disease course is more severe. The CFA component of the EAE induction regimen causes generalized inflammation, promoting expansion of Th40 cells and infiltration of the CNS, while MOG-antigen shapes the antigen-specific TCR repertoire. Those events are both necessary to precipitate disease. In MS, viral infections or trauma may induce generalized inflammation in susceptible individuals with subsequent disease onset. It will be important to further understand the events leading up to disease onset and to elucidate the contributions of the Th40 T cell subset. Also, evaluating Th40 levels as predictors of disease onset would be highly useful because if either the generalized inflammation event or the TCR-honing can be interrupted, disease onset may be prevented.

CD40与CD154的相互作用在自身免疫性疾病中发挥关键调控作用，而CD4阳性T细胞在多发性硬化症（Multiple Sclerosis, MS）的实验性自身免疫性脑脊髓炎（Experimental Autoimmune Encephalomyelitis, EAE）模型中占据核心致病地位。表达CD40的CD4阳性T细胞（Th40）在1型糖尿病中具有致病性，但此前尚未在EAE模型中得到相关评估。本研究证实，相较于传统CD4阳性T细胞，Th40细胞可引发更为快速且病情更严重的EAE病程。过继转移的Th40细胞可定植于中枢神经系统（Central Nervous System, CNS）病变部位，并与广泛的脱髓鞘损伤密切相关。来自EAE诱导供体的原代Th40细胞无需进一步体外扩增，亦无需向受体动物施加EAE诱导方案，即可过继转移诱发EAE——此前尚无使用原代、非TCR转基因供体细胞完成该操作的报道。若将Th40供体细胞与弗氏完全佐剂（Complete Freund’s Adjuvant, CFA）共同注射至受体动物体内，疾病病程将进一步加重。EAE诱导方案中的弗氏完全佐剂组分可引发全身性炎症，促进Th40细胞的扩增与中枢神经系统浸润，而髓鞘少突胶质细胞糖蛋白（Myelin Oligodendrocyte Glycoprotein, MOG）抗原则可塑造抗原特异性T细胞受体（T cell receptor, TCR）库。上述两类事件均为诱发疾病的必要条件。在多发性硬化症中，病毒感染或创伤可诱发易感个体出现全身性炎症，进而引发疾病发作。进一步阐明疾病发作前的相关分子与细胞事件，以及Th40 T细胞亚群的致病贡献，具有重要科学意义。此外，将Th40细胞水平作为疾病发作的预测标志物也极具应用价值：若能阻断全身性炎症事件或TCR库塑造过程，或可有效阻止疾病发作。