{"doi":"10.3389/fimmu.2022.899975","title":"mTORC1 Inhibition Protects Human Regulatory T Cells From Granzyme-B-Induced Apoptosis","abstract":"Regulatory T cells (T regs ) have shown great promise as a means of cellular therapy in a multitude of allo- and auto-immune diseases—due in part to their immunosuppressive potency. Nevertheless, the clinical efficacy of human T regs in patients has been limited by their poor in vivo homeostasis. To avert apoptosis, T regs require stable antigenic (CD3ζ/T-cell-receptor-mediated), co-stimulatory (CD28-driven), and cytokine (IL-2-dependent) signaling. Notably, this sequence of signals supports an activated T reg phenotype that includes a high expression of granzymes, particularly granzyme B (GrB). Previously, we have shown that aside from the functional effects of GrB in lysing target cells to modulate allo-immunity, GrB can leak out of the intracellular lysosomal granules of host T regs , initiating pro-apoptotic pathways. Here, we assessed the role of inhibiting mechanistic target of rapamycin complex 1 (mTORC1), a recently favored drug target in the transplant field, in regulating human T reg apoptosis via GrB. Using ex vivo models of human T reg culture and a humanized mouse model of human skin allotransplantation, we found that by inhibiting mTORC1 using rapamycin, intracytoplasmic expression and functionality of GrB diminished in host T regs ; lowering human T reg apoptosis by in part decreasing the phosphorylation of S6K and c-Jun. These findings support the already clinically validated effects of mTORC1 inhibition in patients, most notably their stabilization of T reg bioactivity and in vivo homeostasis.","journal":"Frontiers in Immunology","year":2022,"id":280144,"datarank":0.38474240361923057,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.0,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9453,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":282630,"name":"Hazim Allos","orcid":"0000-0001-7335-9098","position":1,"is_corresponding":false},{"id":282636,"name":"Basmah S. Al Dulaijan","orcid":"0000-0001-8007-359X","position":2,"is_corresponding":false},{"id":896103,"name":"Gandolina Melhem","orcid":"0009-0009-1838-7745","position":3,"is_corresponding":false},{"id":282628,"name":"Ina Sulkaj","orcid":"0000-0002-2494-8942","position":4,"is_corresponding":false},{"id":282631,"name":"Juliano Alhaddad","orcid":"0000-0002-1461-7955","position":5,"is_corresponding":false},{"id":954189,"name":"Anis J. Saad","orcid":"0000-0003-2402-2522","position":6,"is_corresponding":false},{"id":954190,"name":"Christa Deban","orcid":"0000-0001-7853-7041","position":7,"is_corresponding":false},{"id":447945,"name":"Philip Chu","orcid":"0009-0002-2150-9861","position":8,"is_corresponding":false},{"id":282635,"name":"John Y. Choi","orcid":"0000-0002-9299-3921","position":9,"is_corresponding":false},{"id":282632,"name":"Branislav Kollár","orcid":"0000-0001-6668-7798","position":10,"is_corresponding":false},{"id":282640,"name":"Bohdan Pomahač","orcid":"0000-0003-3703-8240","position":11,"is_corresponding":false},{"id":56888,"name":"Leonardo V. Riella","orcid":"0000-0002-7636-3196","position":12,"is_corresponding":false},{"id":247121,"name":"Stefan P. Berger","orcid":"0000-0003-2228-4676","position":13,"is_corresponding":false},{"id":614252,"name":"Jan‐Stephan Sanders","orcid":"0000-0002-0904-3969","position":14,"is_corresponding":false},{"id":253642,"name":"Judy Lieberman","orcid":"0000-0002-6200-4715","position":15,"is_corresponding":false},{"id":328012,"name":"Li Li","orcid":"0000-0003-2342-3658","position":16,"is_corresponding":false},{"id":282643,"name":"Jamil Azzi","orcid":"0000-0002-6909-4645","position":17,"is_corresponding":false},{"id":282627,"name":"Siawosh K. 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