Type I Interferon Transcriptional Network Regulates Expression of Coinhibitory Receptors in Human T cells

Tomokazu S Sumida, Shai Dulberg, Jonas Schupp, Helen A Stillwell, Pierre-Paul Axisa, Michela Comi, Matthew Lincoln, Avraham Unterman, Naftali Kaminski, Asaf Madi, Vijay K Kuchroo, David A Hafler

Research output: Contribution to journalArticle

Abstract

While inhibition of T cell co-inhibitory receptors has revolutionized cancer therapy, the mechanisms governing their expression on human T cells have not been elucidated. Type 1 interferon (IFN-I) modulates T cell immunity in viral infection, autoimmunity, and cancer, and may facilitate induction of T cell exhaustion in chronic viral infection 1,2 . Here we show that IFN-I regulates co-inhibitory receptors expression on human T cells, inducing PD-1/TIM-3/LAG-3 while surprisingly inhibiting TIGIT expression. High-temporal-resolution mRNA profiling of IFN-I responses enabled the construction of dynamic transcriptional regulatory networks uncovering three temporal transcriptional waves. Perturbation of key transcription factors on human primary T cells revealed both canonical and non-canonical IFN-I transcriptional regulators, and identified unique regulators that control expression of co-inhibitory receptors. To provide direct in vivo evidence for the role of IFN-I on co-inhibitory receptors, we then performed single cell RNA-sequencing in subjects infected with SARS-CoV-2, where viral load was strongly associated with T cell IFN-I signatures. We found that the dynamic IFN-I response in vitro closely mirrored T cell features with acute IFN-I linked viral infection, with high LAG3 and decreased TIGIT expression. Finally, our gene regulatory network identified SP140 as a key regulator for differential LAG3 and TIGIT expression. The construction of co-inhibitory regulatory networks induced by IFN-I with identification of unique transcription factors controlling their expression may provide targets for enhancement of immunotherapy in cancer, infectious diseases, and autoimmunity.

Original languageEnglish
JournalbioRxiv : the preprint server for biology
DOIs
StatePublished - 31 Oct 2020

Fingerprint

Dive into the research topics of 'Type I Interferon Transcriptional Network Regulates Expression of Coinhibitory Receptors in Human T cells'. Together they form a unique fingerprint.

Cite this