NK Regulation

"Consistent with this, CD107a/b⁺ NK cells exhibited higher Siglec-9 expression compared with CD107a/b⁻ cells. Siglec-9 is a member of the glyco-immune checkpoint family and has been implicated in the regulation of NK function. Previous studies have reported that Siglec-9⁺ NK cells display enhanced ADCC activity in the context of HIV infection, and a similar association has been described in SARS-CoV-2 infection. The enrichment of Siglec-9 within the CD107a/b⁺ population may therefore indicate that this NK subpopulation is preferentially engaged during antibody-mediated antiviral responses. Although the precise mechanistic contribution of Siglec-9 in this experimental system remains to be clarified, the results are consistent with the possibility that Siglec-9⁺ NK cells contribute to antibody-dependent viral control during SARS-CoV-2 infection. The study also revealed a concurrent increase in inhibitory and activating receptor expression within NK-cell clusters enriched in the CD107a/b⁺ population. This receptor expression pattern may reflect features associated with NK-cell education rather than strictly opposing regulatory states. NK-cell education, mediated through interactions between inhibitory receptors and self-MHC class I molecules, has been proposed to modulate NK-cell responsiveness by shaping activation thresholds and influencing downstream signaling capacity. Elevated inhibitory receptor expression has been associated with functionally competent NK cells, although such expression alone does not define functional state. Educated NK cells can also exhibit increased expression of activating receptors, including NKG2D, NKp30, NKp46, and DNAM-1, during maturation. Thus, the simultaneous expression of inhibitory and activating receptors may be compatible with an NK education-associated phenotype, while additional factors likely contribute to NK-cell functional diversity. Reduced CD16 expression was observed in CD107a/b⁺-enriched metaclusters, particularly metaclusters 2 and 9. CD16/FcγRIIIa is a major activating Fc receptor that mediates ADCC by recognizing the Fc portion of IgG antibodies bound to target cells. However, surface CD16 expression is dynamically regulated during NK-cell activation and can be reduced through ectodomain shedding, including ADAM17-mediated cleavage. The reduced CD16 signal may therefore reflect activation-associated CD16 downregulation rather than the absence of CD16-dependent ADCC activity. The functional consequences of CD16 shedding may be context-dependent: ADAM17 inhibition can preserve CD16 expression and enhance CD16-dependent NK-cell activation, whereas CD16 shedding may also facilitate NK-cell detachment and serial target engagement during rituximab-dependent ADCC. The impact of limiting CD16 shedding on anti-Spike antibody-mediated NK-cell responses against SARS-CoV-2 remains to be determined."