Elevated CD38 expression on STAT1 GOF CD8+T cells – a potential driver of CD8+ T cell dysregulation?

STAT1 has a central role in relaying signals from type I, II and III interferons (IFN), thus contributing to the antiviral immune response. Working in tandem, CD8+ T cells (CD8T) are key mediators of the adaptive immune response to viral infections. In patients with STAT1 gain of function (GOF) syndrome there is an increase in viral infections, as part of their immune dysregulatory phenotype. However, there is currently a limited understanding of how increased STAT1 signaling might alter CD8T function, potentially impairing anti-viral mechanisms. We thus aim to define the extent and nature of CD8T dysfunction and underlying mechanisms in STAT1 GOF patients. We collected multi-modal high-dimensional immune profiling and functional data including phosphoflow on peripheral blood mononuclear cells (PBMCs) from 24 STAT1GOF patients and age matched controls. 7 Aicardi-Goutières-Syndrome (AGS) patients were included as a comparison population. These cohorts allow us to differentiate the effects of increased type I IFN signaling vs chronic STAT1 activity on CD8T function. STAT1 GOF CD8T showed signs of immune dysregulation including reduced production of IFN-γ and TNF-α upon phorbol-myristate-acetate (PMA) and ionomycin stimulation. High-dimensional immune profiling revealed many activation markers altered on STAT1 GOF CD8T. CD38 was overall significantly elevated, with CD4T and CD8T most affected in STAT1GOF patients. This is also seen to a lesser extent in AGS patients. CD38 was most efficiently induced by T cell receptor (TCR) stimulation in combination with type I interferon in both healthy control and STAT1GOF CD8 T in vitro. Upon further analysis it was the STAT1hi CD8T, known to be elevated in STAT1GOF, that most dynamically upregulated CD38. Conclusion and Outlook: In STAT1 GOF, a model of chronic STAT1 signaling, we found increased expression of CD38 on CD8T. CD38 acts as an ectoenzyme that consumes nicotinamide adenine dinucleotide (NAD+). Elevated CD38 and low NAD+ have been associated with states of immune dysregulation. We thus suggest CD38 as a promising candidate present on STAT1GOF CD8T that might alter NAD+ levels. This could be a potential novel mechanism underlying the immune dysregulation present in STAT1GOF patients.