Evidence that the Density of Self Peptide-MHC Ligands Regulates T-Cell Receptor Signaling

Noncognate or self peptide-MHC (pMHC) ligands productively interact with T-cell receptor (TCR) and are always in a large access over the cognate pMHC on the surface of antigen presenting cells. We assembled soluble cognate and noncognate pMHC class I (pMHC-I) ligands at designated ratios on various scaffolds into oligomers that mimic pMHC clustering and examined how multivalency and density of the pMHCs in model clusters influences the binding to live CD8 T cells and the kinetics of TCR signaling. Our data demonstrate that the density of self pMHC-I proteins promotes their interaction with CD8 co-receptor, which plays a critical role in recognition of a small number of cognate pMHC-I ligands. This suggests that MHC clustering on live target cells could be utilized as a sensitive mechanism to regulate T cell responsiveness.

异源或自身肽-MHC（peptide-MHC，pMHC）配体可与T细胞受体（T-cell receptor，TCR）发生功能性结合，且在抗原呈递细胞表面的丰度始终高于同源pMHC配体。我们将可溶性同源与异源I类肽-MHC（pMHC-I）配体以指定比例组装于多种支架之上，构建出模拟pMHC聚集状态的寡聚体；借此探究模型聚集体中pMHC的多价性与密度，如何影响其与活体细胞CD8阳性T细胞的结合，以及TCR信号传导的动力学过程。本研究数据表明，自身pMHC-I蛋白的密度可促进其与CD8共受体（CD8 co-receptor）的相互作用，而该过程在识别少量同源pMHC-I配体时发挥关键作用。这一发现提示，活体细胞靶标表面的MHC聚集现象可作为一种灵敏的调控机制，用以调节T细胞的应答能力。