{"doi":"10.1101/2020.10.30.362947","title":"Type I Interferon Transcriptional Network Regulates Expression of Coinhibitory Receptors in Human T cells","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":119839,"datarank":0.41588830833596724,"base_score":2.772588722239781,"endowment":2.772588722239781,"self_citation_contribution":0.41588830833596724,"citation_network_contribution":0.0,"self_endowment_contribution":0.41588830833596724,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":241908,"name":"Shai Dulberg","orcid":"0000-0001-8304-5324","position":1,"is_corresponding":false},{"id":34716,"name":"Jonas C. Schupp","orcid":"0000-0002-7714-8076","position":2,"is_corresponding":false},{"id":49158,"name":"Helen A. Stillwell","orcid":"0000-0003-2178-3473","position":3,"is_corresponding":false},{"id":291529,"name":"Pierre‐Paul Axisa","orcid":"0000-0003-1446-3922","position":4,"is_corresponding":false},{"id":555953,"name":"Michela Comi","orcid":"0000-0002-0109-4868","position":5,"is_corresponding":false},{"id":49153,"name":"Matthew R. Lincoln","orcid":"0000-0003-2962-6253","position":6,"is_corresponding":false},{"id":555954,"name":"Avraham Unterman","orcid":"0000-0003-0965-3326","position":7,"is_corresponding":false},{"id":12162,"name":"Naftali Kaminski","orcid":"0000-0001-5917-4601","position":8,"is_corresponding":false},{"id":7864,"name":"Asaf Madi","orcid":"0000-0003-3441-3228","position":9,"is_corresponding":false},{"id":6940,"name":"Vijay K. Kuchroo","orcid":"0000-0001-7177-2110","position":10,"is_corresponding":false},{"id":37332,"name":"David A. Hafler","orcid":"0000-0003-4664-535X","position":11,"is_corresponding":false},{"id":49152,"name":"Tomokazu S. Sumida","orcid":"0000-0002-9806-2642","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:14:13.002105Z","pmid":"33140047","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}