1. Type I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells
- Author
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Matthew R Lincoln, Pierre-Paul Axisa, Naftali Kaminski, Avraham Unterman, Michela Comi, David A. Hafler, Shai Dulberg, Asaf Madi, Jonas C. Schupp, Vijay K. Kuchroo, Tomokazu Sumida, and Helen A Stillwell
- Subjects
LAG3 ,Receptor expression ,T cell ,medicine.medical_treatment ,T-Lymphocytes ,Gene regulatory network ,Receptors, Antigen, T-Cell ,Biology ,Article ,immunology ,TIGIT ,Interferon ,medicine ,Immunology and Allergy ,Humans ,Gene Regulatory Networks ,Receptors, Immunologic ,Receptor ,Transcription factor ,T cell immunity ,SARS-CoV-2 ,COVID-19 ,type 1 interferon ,Immunotherapy ,Cell biology ,medicine.anatomical_structure ,Interferon Type I ,coinhibitory receptors ,medicine.drug - 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 infection1,2. 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.
- Published
- 2020