TY - UNPB
T1 - Antigen and checkpoint receptor recalibration of T cell receptor signal strength
AU - Elliot, Thomas A.E.
AU - Jennings, Emma K.
AU - Lecky, David A.J.
AU - Thawait, Natasha
AU - Flores-Langarica, Adriana
AU - Wraith, David C.
AU - Bending, David
PY - 2021/3/2
Y1 - 2021/3/2
N2 - 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 as a digital read-out of NFAT pathway activity, we identify the rapid quantitative and qualitative changes that occur in CD4+ T cells in response to a range of TCR signalling strengths. We demonstrate that the time and dose dependent programming of distinct co-inhibitory receptors rapidly re-calibrates T cell activation thresholds. By developing a new in vivo model, we analyse the immediate effects of ICB on T cell re-activation. Our findings reveal that anti-PD1 but not anti-Lag3 immunotherapy leads to an increased TCR signal strength. We define a strong TCR signal metric of five genes specifically upregulated by anti-PD1 in T cells (TCR.strong), which can stratify clinical outcomes during anti-PD1 monotherapy in melanoma patients. Our study therefore reveals how analysis of TCR signal strength – and its manipulation – can provide powerful metrics for monitoring outcomes to immunotherapy.
AB - 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 as a digital read-out of NFAT pathway activity, we identify the rapid quantitative and qualitative changes that occur in CD4+ T cells in response to a range of TCR signalling strengths. We demonstrate that the time and dose dependent programming of distinct co-inhibitory receptors rapidly re-calibrates T cell activation thresholds. By developing a new in vivo model, we analyse the immediate effects of ICB on T cell re-activation. Our findings reveal that anti-PD1 but not anti-Lag3 immunotherapy leads to an increased TCR signal strength. We define a strong TCR signal metric of five genes specifically upregulated by anti-PD1 in T cells (TCR.strong), which can stratify clinical outcomes during anti-PD1 monotherapy in melanoma patients. Our study therefore reveals how analysis of TCR signal strength – and its manipulation – can provide powerful metrics for monitoring outcomes to immunotherapy.
U2 - 10.1101/2021.03.02.431957
DO - 10.1101/2021.03.02.431957
M3 - Working paper
SP - 1
EP - 48
BT - Antigen and checkpoint receptor recalibration of T cell receptor signal strength
PB - bioRxiv
ER -