Here today--not gone tomorrow: roles for activating receptors in sustaining NK cells during viral infections

Abstract

The conclusive evidence supporting a role for NK cells in defense against viruses has been obtained under conditions of NK cell deficiencies prior to infections. NK cell proliferation can be induced during infections, but the advantages of resulting expansion have been unclear because NK cell basal frequency is already high. However, NK cell decreases are also observed during certain conditions of viral infection. Given the range of potent antiviral and immunoregulatory functions of NK cells, such "disappearance" dramatically changes the resources available to the host. New studies demonstrate that proliferation dependent on activating receptors for virus-induced ligands is key for NK cell maintenance, and allows their continued availability for control of adaptive immune responses and immunopathology. This pathway for sustaining NK cells may represent a system used generally to select subsets for rescue during homeostatic purging. In the case of NK cells, though, nonselection limits continued access to the many beneficial functions of NK cells. The observations resolve the long-standing conundrum of reported NK cell increases and decreases during viral infections. Moreover, they demonstrate a previously unappreciated role for activating receptors, i.e. to keep NK cells here today and also tomorrow.

Figure 1

Model for contributions made to sustaining NK cells and hence their NK cell functions by activating receptors and virus-induced ligand pairs. Genetic variability in the expression of particular activating receptors in different individuals, as well as differences in virus induction of ligands, helps explain the paradoxical reports of increases in NK cell subsets and decreases in overall NK cells under different conditions of infection. If the conditions of infection fail to result in the induction of an activating receptor and virus-induced pair, NK cells will be decreasing as the infection advances. If a receptor ligand pair is present, the NK cell subset expressing the activating receptor for the virus-induced ligand will be preferentially stimulated and marked for rescue from purging. Thus, proliferation of NK cells through activating receptors provides a mechanism to allow their continued access and contributions to a variety of responses during infection, including documented antiviral and immunoregulatory effects mediated through killing or cytokine/chemokine production. (Red arrows represent decreases in subsets failing to be stimulated, and green arrows represent induction of proliferation and maintenance.)