Antigen and checkpoint receptor recalibration of T cell receptor signal strength

Research output: Working paper

Standard

Antigen and checkpoint receptor recalibration of T cell receptor signal strength. / Elliot, Thomas A.E.; Jennings, Emma K.; Lecky, David A.J.; Thawait, Natasha; Flores-Langarica, Adriana; Wraith, David C.; Bending, David.

bioRxiv, 2021. p. 1-48.

Research output: Working paper

Harvard

APA

Elliot, T. A. E., Jennings, E. K., Lecky, D. A. J., Thawait, N., Flores-Langarica, A., Wraith, D. C., & Bending, D. (2021). Antigen and checkpoint receptor recalibration of T cell receptor signal strength. (pp. 1-48). bioRxiv. https://doi.org/10.1101/2021.03.02.431957

Vancouver

Elliot TAE, Jennings EK, Lecky DAJ, Thawait N, Flores-Langarica A, Wraith DC et al. Antigen and checkpoint receptor recalibration of T cell receptor signal strength. bioRxiv. 2021 Mar 2, p. 1-48. https://doi.org/10.1101/2021.03.02.431957

Author

Elliot, Thomas A.E. ; Jennings, Emma K. ; Lecky, David A.J. ; Thawait, Natasha ; Flores-Langarica, Adriana ; Wraith, David C. ; Bending, David. / Antigen and checkpoint receptor recalibration of T cell receptor signal strength. bioRxiv, 2021. pp. 1-48

Bibtex

@techreport{221ef0b3ac7a447cb451e0b59499f0bc,
title = "Antigen and checkpoint receptor recalibration of T cell receptor signal strength",
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.",
author = "Elliot, {Thomas A.E.} and Jennings, {Emma K.} and Lecky, {David A.J.} and Natasha Thawait and Adriana Flores-Langarica and Wraith, {David C.} and David Bending",
year = "2021",
month = mar,
day = "2",
doi = "10.1101/2021.03.02.431957",
language = "English",
pages = "1--48",
publisher = "bioRxiv",
type = "WorkingPaper",
institution = "bioRxiv",

}

RIS

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 -