Antigen and checkpoint receptor engagement recalibrates T cell receptor signal strength
- Resource Type
- Authors
- 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
- Source
- Immunity
- Subject
- 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
- Language
- ISSN
- 1097-4180
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.