{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Eskandari SK"],"funding":["American Heart Association","Qatar Foundation","NIAID NIH HHS","American Diabetes Association","National Institutes of Health"],"pagination":["899975"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9229986"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["13"],"pubmed_abstract":["Regulatory T cells (T<sub>regs</sub>) 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<sub>regs</sub> in patients has been limited by their poor <i>in vivo</i> homeostasis. To avert apoptosis, T<sub>regs</sub> 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<sub>reg</sub> 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<sub>regs</sub>, 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<sub>reg</sub> apoptosis <i>via</i> GrB. Using <i>ex vivo</i> models of human T<sub>reg</sub> 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<sub>regs</sub>; lowering human T<sub>reg</sub> 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<sub>reg</sub> bioactivity and <i>in vivo</i> homeostasis."],"journal":["Frontiers in immunology"],"pubmed_title":["mTORC1 Inhibition Protects Human Regulatory T Cells From Granzyme-B-Induced Apoptosis."],"pmcid":["PMC9229986"],"funding_grant_id":["R01 AI134842"],"pubmed_authors":["Pomahac B","Chu P","Kollar B","Deban C","Sulkaj I","Sanders JSF","Melhem G","Saad AJ","Allos H","Azzi JR","Li L","Al Dulaijan BS","Berger SP","Eskandari SK","Riella LV","Alhaddad JB","Choi JY","Lieberman J"],"additional_accession":[]},"is_claimable":false,"name":"mTORC1 Inhibition Protects Human Regulatory T Cells From Granzyme-B-Induced Apoptosis.","description":"Regulatory T cells (T<sub>regs</sub>) 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<sub>regs</sub> in patients has been limited by their poor <i>in vivo</i> homeostasis. To avert apoptosis, T<sub>regs</sub> 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<sub>reg</sub> 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<sub>regs</sub>, 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<sub>reg</sub> apoptosis <i>via</i> GrB. Using <i>ex vivo</i> models of human T<sub>reg</sub> 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<sub>regs</sub>; lowering human T<sub>reg</sub> 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<sub>reg</sub> bioactivity and <i>in vivo</i> homeostasis.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022","modification":"2025-04-04T19:13:23.343Z","creation":"2025-04-04T19:13:23.343Z"},"accession":"S-EPMC9229986","cross_references":{"pubmed":["35757726"],"doi":["10.3389/fimmu.2022.899975"]}}