Elliot et al. used a reporter mouse model, Tg4 Nr4a3-Tocky, to monitor the temporal dynamics of TCR signaling, track T cell activation in vivo, and identify quantitative and qualitative changes in T cells receiving different strengths of TCR signaling. Several key transcriptional programs were identified, and expression of co-inhibitory molecules, particularly PD-1, rapidly recalibrated the TCR activation threshold of T cells. Anti-PD-1 increased the probability of T cell reactivation and resulted in stronger TCR signaling. A signature for genes upregulated in response to strong TCR signaling could be used to stratify responses to anti-PD-1 in patients with melanoma.
Contributed by Lauren Hitchings
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.
Author Info: (1) Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. (2) Infrastructure and Facilities, College
Author Info: (1) Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. (2) Infrastructure and Facilities, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. (3) Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. (4) Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: d.a.bending@bham.ac.uk.
