Human natural killer cells mediate adaptive immunity to viral antigens

Abstract

Vaccination or childhood infection elicits antigen-specific, long-lived immunological memory in human natural killer cells. Recall responses by human NK cells One of the traditional dividing lines separating innate and adaptive immunity was the restriction of immune memory to adaptive immune cells. This paradigm has been challenged by accumulating evidence that memory responses can be evoked in natural killer (NK) cells from experimental animals, including mice and nonhuman primates. To determine whether human NK cells also exhibit memory responses, Nikzad et al. analyzed NK cells recovered from humanized mice or NK cells found in the viral antigen-challenged skin of adult volunteers who had chickenpox as children. Antigen-specific recall responses by human NK cells were observed in both experimental systems. These findings suggest that human NK memory responses contribute to acquired host protection after either natural infections or vaccine administration. Adaptive immune responses are defined as antigen sensitization–dependent and antigen-specific responses leading to establishment of long-lived immunological memory. Although natural killer (NK) cells have traditionally been considered cells of the innate immune system, mounting evidence in mice and nonhuman primates warrants reconsideration of the existing paradigm that B and T cells are the sole mediators of adaptive immunity. However, it is currently unknown whether human NK cells can exhibit adaptive immune responses. We therefore tested whether human NK cells mediate adaptive immunity to virally encoded antigens using humanized mice and human volunteers. We found that human NK cells displayed vaccination-dependent, antigen-specific recall responses in vitro, when isolated from livers of humanized mice previously vaccinated with HIV-encoded envelope protein. Furthermore, we discovered that large numbers of cytotoxic NK cells with a tissue-resident phenotype were recruited to sites of varicella-zoster virus (VZV) skin test antigen challenge in VZV-experienced human volunteers. These NK-mediated recall responses in humans occurred decades after initial VZV exposure, demonstrating that NK memory in humans is long-lived. Our data demonstrate that human NK cells exhibit adaptive immune responses upon vaccination or infection. The existence of human memory NK cells may allow for the development of vaccination-based approaches capable of establishing potent NK-mediated memory functions contributing to host protection.