Amplified STAT3 signaling alters expression of CD39 in STAT3 gain-of-function (STAT3 GOF) and in healthy donor CD8 +T cells

Abstract It is still unknown whether primary immune regulatory disorders (PIRD) due to genetic variants that amplify T cell receptor and/or inflammatory cytokine signaling yield exhaustion. Here, we investigate the impact of dysregulated on CD8 +T cells in STAT3 gain-of-function (STAT3 GOF) patients. Immune profiling via 43-parameter CyTOF reveals altered differentiation, including loss naïve cells, increased frequency effector memory and EMRAcells, downregulation markers stemness (i.e., TCF-1 CD127) GOF. Additionally, GOF demonstrate decreased IL-2 production proliferation. We identify expression ecto-enzyme, CD39, which has been reported exhausted hydrolyzes extracellular ATP, from patients a mouse model To signals regulating healthy donor were cultured with STAT3-activating cytokines alone but did not upregulate CD39. However, TCR engagement led robust CD39 was further augmented cytokines. Specifically, upregulation occurs pSTAT3 Y705+cells. Finally, sorted +CD8 hydrolyzed ATP suppressed proliferation compared −CD8 cells. These data suggest may play role levels thus contribute exhaustion, will be explored future work. Understanding how impacts function these rare can improve our understanding this complex disease insights into shared aspects dysfunction found more common diseases. HHMI Gilliam Fellowship for Advanced Studies (GT15736) Penn Presidential PIDTC (Henrickson Lab) IDF NIH NIAD K08AI135091 Burroughs Wellcome Fund CAMS