Type I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells

Although inhibition of T cell coinhibitory receptors has revolutionized cancer therapy, the mechanisms governing their expression on human T cells have not been elucidated. In the present study, we show that type 1 interferon (IFN-I) regulates coinhibitory receptor expression on human T cells, inducing PD-1/TIM-3/LAG-3 while inhibiting TIGIT expression. High-temporal-resolution mRNA profiling of IFN-I responses established the dynamic regulatory networks uncovering three temporal transcriptional waves. Perturbation of key transcription factors (TFs) and TF footprint analysis revealed two regulator modules with different temporal kinetics that control expression of coinhibitory receptors and IFN-I response genes, with SP140 highlighted as one of the key regulators that differentiates LAG-3 and TIGIT expression. Finally, we found that the dynamic IFN-I response in vitro closely mirrored T cell features in acute SARS-CoV-2 infection. The identification of unique TFs controlling coinhibitory receptor expression under IFN-I response may provide targets for enhancement of immunotherapy in cancer, infectious diseases and autoimmunity. Sumida et al. resolve the human T cell transcriptional response to type I interferon stimulation at high temporal resolution and reveal a genetic network controlling coinhibitory receptor expression.

Automated summary

This study demonstrates the regulation of coinhibitory receptor expression on human T cells by type 1 interferon (IFN-I) and reveals the dynamic regulatory networks involved. The key transcription factor SP140 is highlighted as one of the regulators that differentiate LAG-3 and TIGIT expression. The study also shows that the in vitro IFN-I response closely mirrors T cell features in acute SARS-CoV-2 infection.