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

By 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

Posted 31 Oct 2020
bioRxiv DOI: 10.1101/2020.10.30.362947

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. ### Competing Interest Statement D.A.H. has received research funding from Bristol-Myers Squibb, Sanofi, and Genentech. He has been a consultant for Bristol Myers Squibb, Compass Therapeutics, EMD Serono, Genentech, and Sanofi Genzyme over the last three years. Further information regarding funding is available on: https://openpaymentsdata.cms.gov/physician/166753/general-payments. V.K.K. has an ownership interest and is a member of the SAB for Tizona Therapeutics. V.K.K. is also a co-founder and has an ownership interest and a member of SAB in Celsius Therapeutics and Bicara Therapeutics. V.K.K.'s interests were reviewed and managed by the Brigham and Women's Hospital and Partners Healthcare in accordance with their conflict of interest policies. N.K. served as a consultant to Biogen Idec, Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Theravance, LifeMax, Three Lake Partners, Optikira, Astra Zeneca over the last 3 years, reports Equity in Pliant and a grant from Veracyte and non-financial support from MiRagen and Astra Zeneca. Has IP on novel biomarkers and therapeutics in IPF licensed to Biotech.

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