Skip to main content
. 2021 Jun 11;22(2):112–123. doi: 10.1038/s41577-021-00558-3

Fig. 1. NK cell differentiation as a framework to understand NK cell antiviral immunity.

Fig. 1

The differentiation status of human natural killer (NK) cells determines their functional response in viral infections. CD56bright NK cells and less differentiated CD56dim NK cells express high levels of NKG2A, natural cytotoxicity receptors (NCRs; NKp30, NKp44 and NKp46) and proinflammatory and antiviral cytokine receptors (IL-12 receptor (IL-12R), IL-18R and type I interferon receptor (IFNAR)). During acute viral infections, with ensuing production of IL-12, IL-18 and type I interferons by other immune cells, less differentiated NK cells are the main NK cell subset to respond. As indicated by black arrows, cytokine stimulation leads to signalling via signal transducer and activator of transcription 1 (STAT1) and STAT4 and PI3K–AKT–mTOR pathways to rapidly induce NK cell cytokine production and proliferation. With increased maturation, circulating CD56bright NK cells undergo a phenotypic shift and their responsiveness during infection becomes altered. As a consequence, more differentiated NK cells are more prone to respond to cytomegalovirus, leading to the expansion of adaptive-like NK cells that express high levels of killer cell immunoglobulin-like receptors (KIRs) and NKG2C. Circulating CD56bright NK cells might also home to tissues, giving rise to tissue-resident NK cells. Their role in the early response to infection remains elusive. However, liver-resident NK cells have been shown to mediate antigen-specific antiviral responses. Alterations in transcription factor expression during NK cell differentiation are indicated within the respective cell nuclei, and a summary of phenotypic changes during NK cell differentiation is depicted in the table. For some receptors, the expression depends on the tissue microenvironment and specific subsets studied and will deviate from what is indicated here (denoted by the asterisk). CLA, cutaneous lymphocyte-associated antigen; HAV, hepatitis A virus; HBV, hepatitis B virus; ISG, interferon-stimulated gene; NA, not available.