Mapping NK cell diversity in response to COVID-19 and mRNA vaccination

Human NK cells exhibit functional heterogeneity, yet the clinical conditions and cellular processes driving this diversity remain insufficiently understood. Here, we report that NK cell diversity emerges during peripheral development, influenced by the divergence of adaptive NK cells from various stages of canonical NK cell maturation during the resolution phase of severe COVID-19. Using scRNA-seq, we analyzed blood NK cells from patients with severe COVID-19 (acute phase and post-intensive care), individuals vaccinated with the SARS-CoV-2 mRNA vaccine (BNT162b2), and healthy donors. The frequencies of immature CD56^bright and proliferating NK cells increased following BNT162b2 vaccination. In contrast, the frequency of adaptive CD56^dim cells was markedly elevated in patients recovering from severe COVID-19, alongside clonal expansion and enhanced mitochondrial oxidative phosphorylation. Trajectory analysis revealed a bifurcation in peripheral NK cell development, with CD56^bright cells diverging into canonical and adaptive CD56^dim subsets during the course of severe COVID-19. Notably, adaptive NK differentiation exhibited transcriptional and signaling profiles analogous to those of T-cell activation. Thus, NK cell diversity is shaped by the induction of an intrinsic adaptive program. These findings uncover the mechanisms underlying NK cell heterogeneity and have implications for medical applications, including the development of immunotherapies that leverage adaptive NK cell functions.