In keeping with their name, natural killer (NK) cells can have direct cytotoxic effects on virus-infected cells when stimulated through activating receptors. But signalling through such receptors can also result in NK cell proliferation. Christine Biron and colleagues now show that the resulting increase in NK cell numbers has an important role in maintaining the peace during viral infection by preventing T cell-mediated immunopathology.

The mouse NK cell activating receptor Ly49H recognizes a ligand from mouse cytomegalovirus (MCMV), and engagement of Ly49H can lead to killing of MCMV-infected cells. To separate the role of Ly49H in direct antiviral effects from other possible roles associated with NK cell proliferation, the authors compared Ly49h−/− mice with mice lacking perforin 1 (Prf1−/− mice), which have defective cytotoxic functions.

Both Ly49h−/− mice and Prf1−/− mice had higher viral loads after infection with MCMV than wild-type mice, but Ly49h−/− mice had decreased numbers of NK cells whereas Prf1−/− mice had increased numbers of NK cells as a result of effects on the rate and duration of NK cell proliferation after infection. The NK cell population in infected Prf1−/− mice was enriched for subsets that express Ly49H and the Ly49H+ NK cells had the highest rate of proliferation. The intrinsic proliferative potential of Ly49H+ and Ly49H− NK cells — as assessed by their response to interleukin-2 (IL-2) in vitro — was equivalent. These results indicate that stimulation of Ly49H is directly responsible for the marked NK cell proliferation that occurs in response to MCMV infection in Prf1−/− mice. Further proof of this was provided by the markedly lower number of NK cells in Ly49h−/−Prf1−/− mice than in Prf1−/− mice after MCMV infection.

To determine whether this NK cell proliferation has any beneficial role, the body weight and survival of infected mice were monitored for extended time periods after MCMV infection. Ly49h−/−Prf1−/− mice had greater and more prolonged weight loss and lower survival rates than Prf1−/− mice despite similar viral titres, which shows that the disease susceptibility was independent of susceptibility to infection. Instead, protection against disease in Prf1−/− mice compared with Ly49h−/−Prf1−/− mice correlated with an increased level of the immunoregulatory cytokine IL-10 in the Prf1−/− mice, which was shown to be produced by the expanded NK cell population. The decreased IL-10 production in Ly49h−/−Prf1−/− mice, resulting from decreased NK cell proliferation, was associated with increased activation of CD8+ T cells. Similarly, antibody-mediated neutralization of IL-10 in Prf1−/− mice resulted in increased CD8+ T cell responses and decreased survival after MCMV infection. Finally, the authors showed that blocking the CD8+ T cell response in MCMV-infected Ly49h−/−Prf1−/− mice had no effect on viral titre but did protect against the lethal effects of infection.

So, in addition to NK cell cytotoxicity, Ly49H has a crucial role in supporting NK cell proliferation to prevent immunopathology caused by the adaptive immune system. The work indicates that activating receptors in general might be important for maintaining NK cell populations during infection to allow their broader functions to be accessed through alternative pathways.