英国伯明翰大学David Bending研究组发现，抗原和检查点受体的结合重新校准T细胞受体的信号强度。2021年9月16日，《免疫》杂志在线发表了这项成果。

利用Nr4a3-Tocky小鼠，研究人员报道了CD4⁺T细胞发生的与T细胞受体（TCR）号强度有关的早期数量和质量变化。研究人员捕捉到不同共抑制受体的剂量和时间依赖性编程如何迅速重新校准T细胞的激活阈值，并直观地看到免疫检查点阻断（ICB）对T细胞再激活的直接影响。

研究结果显示，抗PD1免疫疗法会导致TCR信号强度增加。研究人员定义了一个由T细胞中抗PD1上调的五个基因组成的强TCR信号指标，在对抗PD1治疗的黑色素瘤患者结果进行分层时，该指标优于经典的T细胞激活基因特征。因此，这项研究揭示了对TCR信号强度的分析，以及对它的操作如何为监测免疫疗法的结果提供强有力的指标。

据介绍，TCR信号强度如何调节T细胞功能以及ICB在多大程度上改变了T细胞功能是免疫学的关键问题。

附：英文原文

Title: Antigen and checkpoint receptor engagement recalibrates T cell receptor signal strength

Author: Thomas A.E. Elliot, Emma K. Jennings, David A.J. Lecky, Natasha Thawait, Adriana Flores-Langarica, Alastair Copland, Kendle M. Maslowski, David C. Wraith, David Bending

Issue&Volume: 2021-09-16

Abstract: How T cell receptor (TCR) signal strength modulates T cell function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3-Tocky mice, we characterized early quantitative and qualitative changes that occur in CD4+ T cells in relation to TCR signaling strength. We captured how dose- and time-dependent programming of distinct co-inhibitory receptors rapidly recalibrates T cell activation thresholds and visualized the immediate effects of ICB on T cell re-activation. Our findings reveal that anti-PD1 immunotherapy leads to an increased TCR signal strength. We defined a strong TCR signal metric of five genes upregulated by anti-PD1 in T cells (TCR.strong), which was superior to a canonical T cell activation gene signature in stratifying melanoma patient outcomes to anti-PD1 therapy. Our study therefore reveals how analysis of TCR signal strength—and its manipulation—can provide powerful metrics for monitoring outcomes to immunotherapy.

DOI: 10.1016/j.immuni.2021.08.020

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00352-6