{"doi":"10.1038/s41586-018-0206-z","title":"Induction and transcriptional regulation of the co-inhibitory gene module in T cells","abstract":"The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4<sup>+</sup> T cells promotes autoimmunity, whereas sustained overexpression on CD8<sup>+</sup> T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer<sup>1,2</sup>. Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors. We functionally validated two new co-inhibitory receptors, activated protein C receptor (PROCR) and podoplanin (PDPN). The module of co-inhibitory receptors is co-expressed in both CD4<sup>+</sup> and CD8<sup>+</sup> T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module, and this was validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumour immunity.","journal":"Nature","year":2018,"id":12450,"datarank":0.9177145797062024,"base_score":6.118097198041348,"endowment":6.118097198041348,"self_citation_contribution":0.9177145797062024,"citation_network_contribution":0.0,"self_endowment_contribution":0.9177145797062024,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":453,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0465,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2018-06-01","fair_score":61.25,"fair_percentile":92.70008795074759,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":7864,"name":"Asaf Madi","orcid":"0000-0003-3441-3228","position":1,"is_corresponding":false},{"id":86792,"name":"Takaaki Kondo","orcid":"0000-0002-3272-0841","position":2,"is_corresponding":false},{"id":7836,"name":"Huiyuan Zhang","orcid":"0000-0002-1532-2462","position":3,"is_corresponding":false},{"id":51573,"name":"Nandini Acharya","orcid":null,"position":4,"is_corresponding":false},{"id":34472,"name":"Meromit Singer","orcid":"0000-0002-1755-3598","position":5,"is_corresponding":false},{"id":14738,"name":"Jackson Nyman","orcid":"0000-0001-6151-6930","position":6,"is_corresponding":false},{"id":28702,"name":"Nemanja Despot Marjanovic","orcid":null,"position":7,"is_corresponding":false},{"id":2681,"name":"Monika S. Kowalczyk","orcid":"0000-0003-0525-9196","position":8,"is_corresponding":false},{"id":6927,"name":"Chao Wang","orcid":"0000-0003-3084-6093","position":9,"is_corresponding":false},{"id":58386,"name":"Sema Kurtulus","orcid":null,"position":10,"is_corresponding":false},{"id":7645,"name":"Travis Law","orcid":"0000-0002-7399-3299","position":11,"is_corresponding":false},{"id":51569,"name":"Yasaman Etminan","orcid":null,"position":12,"is_corresponding":false},{"id":50396,"name":"James Nevin","orcid":"0000-0002-8957-7118","position":13,"is_corresponding":false},{"id":98139,"name":"Christopher D. Buckley","orcid":"0000-0001-6924-6402","position":14,"is_corresponding":false},{"id":14742,"name":"Patrick R. Burkett","orcid":"0000-0003-4472-7124","position":15,"is_corresponding":false},{"id":3630,"name":"Jason D. Buenrostro","orcid":"0000-0001-9958-3987","position":16,"is_corresponding":false},{"id":3016,"name":"Ana. C. 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