Sumen Cenk, Dustin Michael L, Davis Mark M
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
J Cell Biol. 2004 Aug 16;166(4):579-90. doi: 10.1083/jcb.200404059.
T cell activation by nonself peptide-major histocompatibility complex (MHC) antigenic complexes can be blocked by particular sequence variants in a process termed T cell receptor antagonism. The inhibition mechanism is not understood, although such variants are encountered in viral infections and may aid immune evasion. Here, we study the effect of antagonist peptides on immunological synapse formation by T cells. This cellular communication process features early integrin engagement and T cell motility arrest, referred to as the "stop signal." We find that synapses formed on membranes presenting antagonist-agonist complexes display reduced MHC density, which leads to reduced T cell proliferation that is not overcome by the costimulatory ligands CD48 and B7-1. Most T cells fail to arrest and crawl slowly with a dense ICAM-1 crescent at the leading edge. Similar aberrant patterns of LFA-1/ICAM-1 engagement in live T-B couples correlate with reduced calcium flux and IL-2 secretion. Hence, antagonist peptides selectively disable MHC clustering and the stop signal, whereas LFA-1 valency up-regulation occurs normally.
非自身肽 - 主要组织相容性复合体（MHC）抗原复合物对T细胞的激活可被特定序列变体在一种称为T细胞受体拮抗作用的过程中阻断。尽管在病毒感染中会遇到此类变体且其可能有助于免疫逃逸，但其抑制机制尚不清楚。在此，我们研究拮抗肽对T细胞免疫突触形成的影响。这种细胞通讯过程的特征是早期整合素结合和T细胞运动停滞，即所谓的“停止信号”。我们发现，在呈现拮抗 - 激动剂复合物的膜上形成的突触显示出MHC密度降低，这导致T细胞增殖减少，且共刺激配体CD48和B7 - 1无法克服这种减少。大多数T细胞无法停滞，并在前缘形成密集的ICAM - 1新月形时缓慢爬行。在活的T - B细胞对中，LFA - 1/ICAM - 1结合的类似异常模式与钙通量减少和IL - 2分泌减少相关。因此，拮抗肽选择性地破坏MHC聚集和停止信号，而LFA - 1价态上调正常发生。
