biostudies-literatureFreytag DAgence Nationale de la Recherche (ANR)Agence Nationale de la Recherchehôpitaux universitaires de strasbourgHHS | NIH | National Institute of Allergy and Infectious DiseasesInstitut National de la Santé et de la Recherche MédicaleUniversité de Strasbourg2438-2461https://www.ebi.ac.uk/biostudies/studies/S-EPMC12423328biostudies-literatureUnknown17(9)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.EMBO molecular medicineLymphopenia drives T cell exhaustion in immunodeficient STING gain-of-function mice.PMC12423328ANR-18-RHUS-0010ANR-14-CE14-0026-04ANR-19-CE15-0028ANR-10-IAHU-01ANR-11-EQPX-022Kirstetter PHopsomer GPala FFreytag DGiorgiutti SCouillin IMertz PBosticardo MKorganow ASNotarangelo LDRieux-Laucat FWadier NAuge FDepauw SCarapito RRiteau NSoulas-Sprauel PfalseLymphopenia drives T cell exhaustion in immunodeficient STING gain-of-function mice.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.2025-01-01T00:00:00Z2025 Sep2026-06-01T23:33:52.789Z2026-05-23T03:07:59.273ZS-EPMC124233284080416310.1038/s44321-025-00292-6