Department of Immunology, Howard Hughes Medical Institute and Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
PLoS Biol. 2010 Sep 14;8(9):e1000481. doi: 10.1371/journal.pbio.1000481.
αβ T cell receptor (TCR) recognition of foreign peptides bound to major histocompatibility complex (pMHC) molecules on the surface of antigen presenting cells is a key event in the initiation of adaptive cellular immunity. In vitro, high-affinity binding and/or long-lived interactions between TCRs and pMHC correlate with high-potency T cell activation. However, less is known about the influence of TCR/pMHC interaction parameters on T cell responses in vivo. We studied the influence of TCR/pMHC binding characteristics on in vivo T cell immunity by tracking CD4(+) T cell activation, effector, and memory responses to immunization with peptides exhibiting a range of TCR/pMHC half-lives and in vitro T cell activation potencies. Contrary to predictions from in vitro studies, we found that optimal in vivo T cell responses occur to ligands with intermediate TCR/pMHC half-lives. The diminished in vivo responses we observed to the ligand exhibiting the longest TCR/pMHC half-life were associated with attenuation of intracellular signaling, expansion, and function over a broad range of time points. Our results reveal a level of control over T cell activation in vivo not recapitulated in in vitro assays and highlight the importance of considering in vivo efficacy of TCR ligands as part of vaccine design.
αβ T 细胞受体 (TCR) 识别与抗原呈递细胞表面主要组织相容性复合体 (pMHC) 分子结合的外来肽是适应性细胞免疫起始的关键事件。在体外，TCR 与 pMHC 之间的高亲和力结合和/或长寿命相互作用与高效力 T 细胞激活相关。然而，关于 TCR/pMHC 相互作用参数对体内 T 细胞反应的影响知之甚少。我们通过跟踪 CD4(+)T 细胞对具有一系列 TCR/pMHC 半衰期和体外 T 细胞激活效力的肽的免疫的激活、效应和记忆反应，研究了 TCR/pMHC 结合特性对体内 T 细胞免疫的影响。与体外研究的预测相反，我们发现，具有中间 TCR/pMHC 半衰期的配体可产生最佳的体内 T 细胞反应。我们观察到对具有最长 TCR/pMHC 半衰期的配体的体内反应减弱，与细胞内信号转导、扩张和功能的衰减有关，涉及广泛的时间点。我们的结果揭示了体内 T 细胞激活的控制水平，这在体外测定中没有重现，并强调了考虑 TCR 配体的体内功效作为疫苗设计的一部分的重要性。
