Antigen and checkpoint receptor recalibration of T cell receptor signal strength

Thomas A.E. Elliot, Emma K. Jennings, David A.J. Lecky, Natasha Thawait, Adriana Flores-Langarica, David C. Wraith, David Bending

Research output: Working paper/PreprintWorking paper

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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 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.
Original languageEnglish
PublisherbioRxiv
Pages1-48
Number of pages48
DOIs
Publication statusPublished - 2 Mar 2021

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