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Human natural killer cell diversity is a metric of immune function associated with less effective antiviral response. The downside of diversity The adaptive immune system exemplifies the benefits of diversity, allowing for individual responses to specific pathogens. Natural killer (NK) cells are diverse at the single-cell level, but the contribution of this diversity to NK cell–mediated immunity has been unclear. Strauss-Albee et al. found that contrary to adaptive immune cells, human NK cell diversity is lower at birth than in adults. Moreover, diversification as a result of antiviral response decreases the flexibility of future antiviral responses. Indeed, high NK cell diversity was associated with increased risk of HIV-1 acquisition in African women. These data suggest that preexisting NK cell diversity should be considered in the context of viral infections. Innate natural killer (NK) cells are diverse at the single-cell level because of variegated expressions of activating and inhibitory receptors, yet the developmental roots and functional consequences of this diversity remain unknown. Because NK cells are critical for antiviral and antitumor responses, a better understanding of their diversity could lead to an improved ability to harness them therapeutically. We found that NK diversity is lower at birth than in adults. During an antiviral response to either HIV-1 or West Nile virus, NK diversity increases, resulting in terminal differentiation and cytokine production at the cost of cell division and degranulation. In African women matched for HIV-1 exposure risk, high NK diversity is associated with increased risk of HIV-1 acquisition. Existing diversity may therefore decrease the flexibility of the antiviral response. Collectively, the data reveal that human NK diversity is a previously undefined metric of immune history and function that may be clinically useful in forecasting the outcomes of infection and malignancy.

Human NK cell repertoire diversity reflects immune experience and correlates with viral susceptibility