Diminished cell proliferation promotes natural killer cell adaptive-like phenotype by limiting Fc epsilon RI gamma expression

Diminished human NK cell proliferation limits Fc epsilon RI gamma expression, leading to an adaptive-like NK cell phenotype, and may have an early prognostic value for COVID-19 disease severity, associated with increased inflammation and higher TGF beta and IFN alpha levels. Human adaptive-like natural killer (NK) cells express low levels of Fc epsilon RI gamma (FcR gamma(-/low)) and are reported to accumulate during COVID-19 infection; however, the mechanism underlying and regulating FcR gamma expression in NK cells has yet to be fully defined. We observed lower FcR gamma protein expression in NK cell subsets from lung transplant patients during rapamycin treatment, suggesting a link with reduced mTOR activity. Further, FcR gamma(-/low) NK cell subsets from healthy donors displayed reduced mTOR activity. We discovered that FcR gamma upregulation is dependent on cell proliferation progression mediated by IL-2, IL-15, or IL-12, is sensitive to mTOR suppression, and is inhibited by TGF beta or IFN alpha. Accordingly, the accumulation of adaptive-like FcR gamma(-/low) NK cells in COVID-19 patients corresponded to increased TGF beta and IFN alpha levels and disease severity. Our results show that an adaptive-like NK cell phenotype is induced by diminished cell proliferation and has an early prognostic value for increased TGF beta and IFN alpha levels in COVID-19 infection associated with disease severity.