Antigen and Checkpoint Receptor Recalibration of T Cell Receptor Signal Strength

• DOI: 10.1101/2021.03.02.431957
• Publication Date: 2021-03-03T00:35:36Z
• Authors: Thomas A.E. Elliot; Emma K. Jennings; David A.J. Lecky; Natasha Thawait; Adriana Flores-La...; David C. Wraith; David Bending
• Keywords: 0303 health sciences; 03 medical and health sciences; 3. Good health

Summary How T cell receptor (TCR) signal strength modulates function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3-Tocky mice as a digital read-out of NFAT pathway activity, we identify the rapid quantitative qualitative changes that occur CD4 + cells response range TCR signalling strengths. We demonstrate time dose dependent programming distinct co-inhibitory receptors rapidly re-calibrates activation thresholds. By developing new vivo model, analyse immediate effects ICB on re-activation. Our findings reveal anti-PD1 but not anti-Lag3 immunotherapy leads an increased strength. define strong metric five genes specifically upregulated (TCR.strong), which can stratify clinical outcomes during monotherapy melanoma patients. study therefore reveals how analysis – its manipulation provide powerful metrics for monitoring immunotherapy. Key Points strength-dependent revealed over Inhibitory expression dynamic, dependent, thresholds PD1 Lag3 unique signature (coined TCR.strong) TCR.strong stratifies patient survival Nivolumab (anti-PD1) therapy