Division of Basic Sciences and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2414-9. doi: 10.1073/pnas.1015433108. Epub 2011 Jan 24.
γδ T cells play important roles in bridging innate and adaptive immunity, but their recognition mechanisms remain poorly understood. Human γδ T cells of the V(δ)1 subset predominate in intestinal epithelia and respond to MICA and MICB (MHC class I chain-related, A and B; MIC) self-antigens, mediating responses to tumorigenesis or viral infection. The crystal structure of an MIC-reactive V(δ)1 γδ T-cell receptor (TCR) showed expected overall structural homology to antibodies, αβ, and other γδ TCRs, but complementary determining region conformations and conservation of V(δ)1 use revealed an uncharacteristically flat potential binding surface. MIC, likewise, serves as a ligand for the activating immunoreceptor natural killer group 2, D (NKG2D), also expressed on γδ T cells. Although MIC recognition drives both the TCR-dependent stimulatory and NKG2D-dependent costimulatory signals necessary for activation, interaction analyses showed that MIC binding by the two receptors was mutually exclusive. Analysis of relative binding kinetics suggested sequential recognition, defining constraints for the temporal organization of γδ T-cell/target cell interfaces.
γδ T 细胞在连接先天免疫和适应性免疫方面发挥着重要作用，但它们的识别机制仍知之甚少。人类肠道上皮细胞中主要存在 V(δ)1 亚群的 γδ T 细胞，其对 MICA 和 MICB（MHC Ⅰ类链相关蛋白 A 和 B；MIC）自身抗原作出反应，介导对肿瘤发生或病毒感染的反应。一种 MIC 反应性 V(δ)1 γδ T 细胞受体（TCR）的晶体结构显示出与抗体、αβ 和其他 γδ TCR 预期的整体结构同源性，但互补决定区构象和 V(δ)1 使用的保守性揭示了一种非典型的平坦潜在结合表面。MIC 同样作为激活免疫受体自然杀伤组 2，D（NKG2D）的配体，NKG2D 也在 γδ T 细胞上表达。尽管 MIC 识别驱动 TCR 依赖性刺激和 NKG2D 依赖性共刺激信号的激活，但相互作用分析表明，两个受体的 MIC 结合是相互排斥的。相对结合动力学分析表明，存在顺序识别，定义了 γδ T 细胞/靶细胞界面的时间组织的约束条件。
