Figure 4. Receptor-mediated regulation of NK cell subset proportions and numbers during viral infection.

The importance of stimulating NK cells through activating receptors to modify the proportions of subsets expressing particular activating receptors and/or sustain their numbers under conditions of extended viral infection is becoming clear. It requires the induction of a ligand by the viral infection and the presence of an activating receptor for the ligand on NK cells. Because the absence of stimulation through activating receptors can result in profound decreases in total NK cell numbers or subsets (red triangles, pointing down) (A) whereas the stimulation through activating receptors can sustain the cells but change the proportions expression particular activating receptors (green triangles, pointing up) (B), the responses have consequences for availability of innate resources in fighting off infection. The example depicted is based on expression of a highly polymorphic and polygenic activating receptor in mouse and human, i.e. Ly49 or KIR. Any requirement for these receptors would allow opportunities for viruses to pass through “holes” in the genetic repertoire of subgroups in a diverse population while others mount effective defense. Use of conserved activating receptors, such as CD94/NKG2C, might act to prime for responses to several viruses and enhance defense against subsequent primary viral infections. Thus, the mechanism of changing the proportions or numbers of NK cells during conditions of extended viral infections is an example of how NK cells are conditioned by experience.