In this preprint, Wilk et al. used single-cell RNA sequencing to compare immune profiles in 7 patients hospitalized with COVID-19 to 6 healthy controls. In CD14+ monocytes from patients, HLA class II expression as well as a pathway associated with DC–NK cell immune crosstalk were reduced, whereas a pathway associated with PD1–PDL1 interactions was increased. A cluster of highly proliferative T cells and NK cells was enriched, with immune checkpoint as well as interferon-stimulated genes uniquely upregulated in NK cells. Collectively, these results indicate that dysregulation of immune crosstalk is associated with severity of COVID-19. Further studies will need to investigate the contribution of these mechanisms to the reduced numbers and impaired functions of NK cells and T cells observed in patients with COVID-19.