{"doi":"10.1101/2021.02.22.432146","title":"Human immunodeficiency reveals GIMAP5 as lymphocyte-specific regulator of senescence","abstract":"Abstract Elucidating the molecular basis of immunodeficiency diseases is a powerful approach to discovering new immunoregulatory pathways in humans. Here we report 10 affected individuals from 4 families with a new immunodeficiency disease comprising of severe progressive lymphopenia, autoimmunity, immunodeficiency, and liver disease due to recessive loss of function variants in “GTPase of immunity-associated proteins” protein 5 (GIMAP5) . We show that the disease involves the progressive loss of naïve T lymphocytes and a corresponding increase in antigen-experienced, but poorly functional and replicatively senescent T cells. In vivo treatment of Gimap5-deficient mice with rapamycin (an inhibitor of mTORC1) significantly restores the fraction of naïve T lymphocytes. Furthermore, a GIMAP5-deficient human patient who was treated with rapamycin (sirolimus) showed a remarkable reduction in spleen/lymph node size. Together, these observations reveal that GIMAP5 plays a critical role in lymphocyte metabolism which is essential for senescence prevention and immune competence, suggesting that an inhibitor of mTORC1 could be a valuable clinical intervention in treating patients deficient for GIMAP5.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":215337,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9457,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":614909,"name":"Michael Leney-Greene","orcid":"0000-0002-3259-1728","position":1,"is_corresponding":false},{"id":810090,"name":"Matthew Lynberg","orcid":"0000-0003-1371-3002","position":2,"is_corresponding":false},{"id":168276,"name":"Xijin Xu","orcid":null,"position":3,"is_corresponding":false},{"id":720356,"name":"Lixin Zheng","orcid":"0000-0002-8838-8665","position":4,"is_corresponding":false},{"id":810091,"name":"Yu Zhang","orcid":"0009-0004-4820-1562","position":5,"is_corresponding":false},{"id":170628,"name":"Helen Matthews","orcid":null,"position":6,"is_corresponding":false},{"id":810092,"name":"Brittany Chao","orcid":"0000-0002-0355-2332","position":7,"is_corresponding":false},{"id":810093,"name":"Aaron Morawski","orcid":"0000-0001-5995-0527","position":8,"is_corresponding":false},{"id":138847,"name":"Ping Jiang","orcid":null,"position":9,"is_corresponding":false},{"id":280622,"name":"Jahnavi Aluri","orcid":"0000-0002-0350-1439","position":10,"is_corresponding":false},{"id":281899,"name":"Elif Karakoç-Aydıner","orcid":"0000-0003-4150-5200","position":11,"is_corresponding":false},{"id":665050,"name":"Ayça Kıykım","orcid":"0000-0001-5821-3963","position":12,"is_corresponding":false},{"id":810094,"name":"John C. 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