Impaired regulation by purinergic signaling axis contributes to CD8+ T cell dysregulation in STAT3 GOF

Gain-of-function (GOF) variants in STAT3 cause a complex disorder characterized by early-onset autoimmunity, lymphoproliferation, recurrent infections, and immune dysregulation. In both primary human and mouse models of STAT3 GOF, CD8+ T cells have been implicated as pathogenic drivers of autoimmunity, though the exact mechanisms remain poorly understood. Here, we found that in patients with STAT3 GOF, CD8+ T cells exist in a phenotypically activated state. Functional assessment revealed that naïve CD8+ T cells have an increased capacity for IFN-g and TNF-a production, with evidence of a Type I/II IFN transcriptional signature. Changes in immunoregulatory pathways revealed dysregulation of the purinergic signaling axis on CD8+ T cells: while CD39 was increased, downstream purinergic family members, CD73 and the adenosine receptor, A2AR, were downregulated, impairing the potential to produce or sense immunosuppressive adenosine. Evaluation of the impact of precision therapy in the form of JAK inhibitors at a cellular and functional level revealed partial normalization of naïve CD8+ T cell dysregulation, including aberrant cytokine production in patients. Our study suggests that a dysregulated purinergic signaling axis plays a key role in CD8+ T cell dysregulation in STAT3 GOF and may have implications for other rare monogenic immune disorders and common inflammatory disorders.