Natural killer (NK) cells are often called 'innate lymphocytes' as they combine innate recognition with the effector mechanisms of T lymphocytes — cytokine secretion (interferon-γ; IFN-γ) and cytotoxic killing. However, in terms of responses to infection, NK cells might be more similar to lymphocytes than previously thought. A report from Dokun et al. in Nature Immunology indicates that, similar to T and B cells, antigen-specific NK cells selectively expand in response to infection.

NK cells identify their targets by integrating signals from their inhibitory and activation receptors. But not all NK cells are created equal. Although their antigen receptors are invariant, NK cell subsets carry distinct complements of receptors. Previously, this group showed that, in mice, an activation receptor of the Ly49 family, Ly49H, confers specific protection against murine cytomegalovirus (MCMV). This implies that NK cells are capable of virus-specific recognition.

So, are Ly49H+ NK cells preferentially activated by MCMV? The present study assessed this in two ways — by scoring for IFN-γ production through intracellular cytokine staining and by measuring NK cell proliferation using a bromodeoxyuridine (BrdU)-incorporation assay. In the early phase of the response to MCMV there is a burst of IFN-γ production by NK cells, which peaks at 36 hours. However, at 2 days post-infection, there are comparable percentages of Ly49H+ and Ly49H− NK cells producing IFN-γ, and there was no difference in the proliferation of the two subsets. By contrast, the authors found that by day 6 post-infection, there has been an outgrowth of Ly49H+ NK cells, and these cells proliferate to a much greater degree than their Ly49H− counterparts.

But is this preferential proliferation actually driven by Ly49H recognition of MCMV? Vaccinia virus infection, which induces NK cell activation, did not cause the selective proliferation of Ly49H+ cells, indicating this might indeed be an MCMV-specific response. In addition, administration of Ly49H antibodies was shown to inhibit bulk NK cell expansion in response to MCMV, which shows that Ly49H has a direct role in MCMV-triggered NK cell activation.

This study provides a new model of NK cell activity in viral infection. Yet it remains to be seen whether this delayed, preferential proliferation of NK cells is itself important for antiviral immunity.