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

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.