Fiche publication
Date publication
août 2025
Journal
EMBO molecular medicine
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CARAPITO Raphaël
,
Dr KIRSTETTER Peggy
Tous les auteurs :
Freytag D, Giorgiutti S, Hopsomer G, Wadier N, Depauw S, Mertz P, Augé F, Carapito R, Couillin I, Korganow AS, Pala F, Bosticardo M, Notarangelo LD, Rieux-Laucat F, Riteau N, Kirstetter P, Soulas-Sprauel P
Lien Pubmed
Résumé
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.
Mots clés
Homeostasis, Lymphopenia, STING, T Cell Exhaustion
Référence
EMBO Mol Med. 2025 08 13;:
