Antigen and checkpoint receptor engagement recalibrates T cell receptor signal strength
| Autor: | Adriana Flores-Langarica, Kendle M. Maslowski, Natasha Thawait, Thomas A.E. Elliot, Alastair Copland, David Bending, Emma K. Jennings, David A.J. Lecky, David C. Wraith |
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| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_treatment
T-Lymphocytes Immunology Programmed Cell Death 1 Receptor Receptors Antigen T-Cell Biology Lymphocyte Activation Article TCR signaling IRF8 Mice Downregulation and upregulation medicine melanoma Immunology and Allergy Animals OX40 Antigens Receptor Immune Checkpoint Inhibitors nivolumab Melanoma T-cell receptor Immunotherapy Gene signature medicine.disease Immune Checkpoint Proteins Cell biology Blockade PD1 Infectious Diseases Gene Expression Regulation ICOS Nr4a3 TCR.strong immunotherapy Protein Binding Signal Transduction |
| Zdroj: | Immunity |
| ISSN: | 1097-4180 |
| Popis: | Summary 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. Graphical abstract Highlights • TCR signal strength drives dynamic and time-dependent changes in CD4+ T cells • Inhibitory receptor expression recalibrates T cell activation thresholds • PD1 blockade leads to a strong TCR signal signature in T cells (TCR.strong) • TCR.strong can stratify melanoma patient responses to anti-PD1 therapy How antigen and immune checkpoint engagement regulate T cell function is not completely understood. Elliot et al. reveal how antigen abundance regulates immune checkpoint expression and recalibrates T cell activation thresholds. PD1 blockade lowers the T cell activation threshold, resulting in a transcriptional signature that stratifies responses to immunotherapy. |
| Databáze: | OpenAIRE |
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