{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Freytag D"],"funding":["Agence Nationale de la Recherche (ANR)","Agence Nationale de la Recherche","hôpitaux universitaires de strasbourg","HHS | NIH | National Institute of Allergy and Infectious Diseases","Institut National de la Santé et de la Recherche Médicale","Université de Strasbourg"],"pagination":["2438-2461"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12423328"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["17(9)"],"pubmed_abstract":["STING gain-of-function (GOF) mutations cause STING-Associated Vasculopathy with onset in Infancy (SAVI), a severe autoinflammatory disease. Mice carrying STING GOF V154M mutation develop profound T cell lymphopenia, partly due to impaired thymic development. To investigate the mechanisms of peripheral T cell dysfunctions, we analyzed transcriptomic and phenotypic profiles of splenic T cells from these mice. We found a terminally exhausted T cell phenotype, established early in life upon entry into the periphery, independent of type I interferons and intrinsic STING activation in T cells or stromal cells. Mechanistically, naive T cells in the lymphopenic periphery experienced heightened stimulation of the IL-7 receptor and TCR, including NFAT pathway, a key factor in T cell exhaustion. Transplantation of STING GOF hematopoietic stem cells with wild-type bone marrow prevented exhaustion in this non-lymphopenic context, placing lymphopenia as a key driver. T cell exhaustion was also observed in lymphopenic mice carrying Rag1 hypomorphic mutations. In conclusion, our results highlight T cell exhaustion induced by lymphopenia and could have important implications for the management of patients with severe immune deficiencies."],"journal":["EMBO molecular medicine"],"pubmed_title":["Lymphopenia drives T cell exhaustion in immunodeficient STING gain-of-function mice."],"pmcid":["PMC12423328"],"funding_grant_id":["ANR-18-RHUS-0010","ANR-14-CE14-0026-04","ANR-19-CE15-0028","ANR-10-IAHU-01","ANR-11-EQPX-022"],"pubmed_authors":["Kirstetter P","Hopsomer G","Pala F","Freytag D","Giorgiutti S","Couillin I","Mertz P","Bosticardo M","Korganow AS","Notarangelo LD","Rieux-Laucat F","Wadier N","Auge F","Depauw S","Carapito R","Riteau N","Soulas-Sprauel P"],"additional_accession":[]},"is_claimable":false,"name":"Lymphopenia drives T cell exhaustion in immunodeficient STING gain-of-function mice.","description":"STING gain-of-function (GOF) mutations cause STING-Associated Vasculopathy with onset in Infancy (SAVI), a severe autoinflammatory disease. Mice carrying STING GOF V154M mutation develop profound T cell lymphopenia, partly due to impaired thymic development. To investigate the mechanisms of peripheral T cell dysfunctions, we analyzed transcriptomic and phenotypic profiles of splenic T cells from these mice. We found a terminally exhausted T cell phenotype, established early in life upon entry into the periphery, independent of type I interferons and intrinsic STING activation in T cells or stromal cells. Mechanistically, naive T cells in the lymphopenic periphery experienced heightened stimulation of the IL-7 receptor and TCR, including NFAT pathway, a key factor in T cell exhaustion. Transplantation of STING GOF hematopoietic stem cells with wild-type bone marrow prevented exhaustion in this non-lymphopenic context, placing lymphopenia as a key driver. T cell exhaustion was also observed in lymphopenic mice carrying Rag1 hypomorphic mutations. In conclusion, our results highlight T cell exhaustion induced by lymphopenia and could have important implications for the management of patients with severe immune deficiencies.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Sep","modification":"2026-06-01T23:33:52.789Z","creation":"2026-05-23T03:07:59.273Z"},"accession":"S-EPMC12423328","cross_references":{"pubmed":["40804163"],"doi":["10.1038/s44321-025-00292-6"]}}