[PDF][PDF] Antigen and checkpoint receptor engagement recalibrates T cell receptor signal strength

TAE Elliot, EK Jennings, DAJ Lecky, N Thawait… - Immunity, 2021 - cell.com
TAE Elliot, EK Jennings, DAJ Lecky, N Thawait, A Flores-Langarica, A Copland
Immunity, 2021cell.com
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 …
Summary
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.
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