Division of Infection and Immunity, Cardiff University, Cardiff CF14 4XN, UK.
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
Sci Rep. 2016 Oct 17;6:35332. doi: 10.1038/srep35332.
CD8 T-cells play a role in the pathogenesis of autoimmune diseases such as multiple sclerosis and type 1 diabetes. However, drugs that target the entire CD8 T-cell population are not desirable because the associated lack of specificity can lead to unwanted consequences, most notably an enhanced susceptibility to infection. Here, we show that autoreactive CD8 T-cells are highly dependent on CD8 for ligand-induced activation via the T-cell receptor (TCR). In contrast, pathogen-specific CD8 T-cells are relatively CD8-independent. These generic differences relate to an intrinsic dichotomy that segregates self-derived and exogenous antigen-specific TCRs according to the monomeric interaction affinity with cognate peptide-major histocompatibility complex class I (pMHCI). As a consequence, "blocking" anti-CD8 antibodies can suppress autoreactive CD8 T-cell activation in a relatively selective manner. These findings provide a rational basis for the development and in vivo assessment of novel therapeutic strategies that preferentially target disease-relevant autoimmune responses within the CD8 T-cell compartment.
CD8 T 细胞在多发性硬化症和 1 型糖尿病等自身免疫性疾病的发病机制中发挥作用。然而，靶向整个 CD8 T 细胞群体的药物并不理想，因为缺乏特异性可能导致不良后果，最明显的是易感染。在这里，我们表明自身反应性 CD8 T 细胞高度依赖 CD8 通过 T 细胞受体 (TCR) 对配体诱导的激活。相比之下，病原体特异性 CD8 T 细胞相对独立于 CD8。这些一般差异与内在二分法有关，根据与同源肽-主要组织相容性复合物 I（pMHCI）的单体相互作用亲和力，将自身衍生和外源性抗原特异性 TCR 分离。因此，“阻断”抗 CD8 抗体可以以相对选择性的方式抑制自身反应性 CD8 T 细胞的激活。这些发现为开发和体内评估新型治疗策略提供了合理的依据，这些策略优先针对 CD8 T 细胞群中与疾病相关的自身免疫反应。
