Human adaptive-like natural killer (NK) cells express low levels of FcεRIγ (FcRγ-/low) and are reported to accumulate during COVID-19 infection; however, the mechanism underlying and regulating FcRγ expression in NK cells has yet to be fully defined. We observed lower FcRγ protein expression in NK cell subsets from lung transplant patients during rapamycin treatment, suggesting a link with reduced mTOR activity. Further, FcRγ-/low NK cell subsets from healthy donors displayed reduced mTOR activity. We discovered that FcRγ 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 TGFβ or IFNα. Accordingly, the accumulation of adaptive-like FcRγ-/low NK cells in COVID-19 patients corresponded to increased TGFβ and IFNα 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 TGFβ and IFNα levels in COVID-19 infection associated with disease severity.
© 2022 Shemesh et al.

The expansion of human FcεRIγ -/low (FcRγ -/low ) natural killer (NK) cells accrues during viral infections; however, the molecular mechanisms regulating FcRγ expression is not well defined and can have implication for host protection and NK cell immunotherapy. Our analysis of NK cell subsets in lung transplant patients during rapamycin treatment revealed significantly lower FcRγ levels in the NK cell population. Moreover, lower FcRγ levels in healthy donors were associated with low mTORC1/C2 activity and low T-bet expression. Cell division suppression by rapamycin or TGFβ suppressed FcRγ upregulation during IL-2 receptor stimulation, whereas promoting NK cell division by co-inhibiting FOXO1 activity restored FcRγ upregulation. These results suggest that the human FcRγ -/low NK cell phenotype is associated with cell division suppression and reduced mTOR activity.