Lymphopenia drives T cell exhaustion in immunodeficient STING gain-of-function mice

STING gain-of-function (GOF) mutations are associated with the severe autoinflammatory disease designated STING Associated Vasculopathy with onset in Infancy (SAVI). Mice with the STING GOF V154M mutation develop profound T cell lymphopenia, partly due to a blockage of T cell development in the thymus. To better characterize the mechanisms of peripheral T cell dysfunctions, we conducted a transcriptomic and phenotypic analysis on sorted splenic CD4+ and CD8+ mature T cells from STING GOF V154M mice. We identify a T cell exhaustion phenotype that manifests at a terminal stage, acquired early in life but only after reaching the peripheral environment. This phenotype is independent of type I interferons and does not rely on intrinsic STING activation in either T cells or stromal cells. Mechanistically, the limited number of mature T cells that reach the periphery appear to be quickly impacted by the lymphopenic environment, experiencing heightened stimulation of the IL-7 receptor and TCR pathways, including the NFAT pathway, a key factor in T cell exhaustion. By performing transplantation experiments with STING GOF long term-hematopoietic stem cells (LT-HSCs) along with supportive wild-type bone marrow (BM) cells, we were able to prevent the T cell exhaustion of STING GOF T cells in the resulting non-lymphopenic context, demonstrating that lymphopenia is a major driver of T cell exhaustion in STING GOF mice. T cell exhaustion, although less severe, was also observed in lymphopenic mice carrying Rag1 hypomorphic mutations. In conclusion, our results, which highlight T cell exhaustion induced by lymphopenia, could have important implications for the management of patients with severe immune deficiencies. Highlights We describe a phenotype of T cell exhaustion in STING GOF V154M mice, which is acquired early in life and in the periphery. STING GOF-associated T cell exhaustion is independent of type I IFNs, and STING GOF/activation in T cells or in stromal cells is not sufficient for T cell exhaustion. Lymphopenia is a major driver of T cell exhaustion in STING GOF mice, and increased antigenic/IL-7 stimulation of T cells in the lymphopenic context of STING GOF mice could be implicated in the induction of T cell exhaustion.