Natural Selection for Killer Receptors and Their MHC Class I Ligands: In Pursuit of Gene Pairs That Fit Well in Tandem

Our understanding of the genetic basis of host resistance to viral infection and disease has progressed significantly over the last century. Numerous genes coding for modifiers of immune functions have been identified, which impact a variety of critical cellular processes, including signaling via lymphocyte receptors and their ligands, signal transduction, cytokine signaling, production and release of cytotoxic effectors, transcriptional regulation, and proliferation. Genome-wide association studies implicate an important role for both highly polymorphic NK cell receptors and their MHC class I ligands in modifying host resistance. These findings indicate NK cells are critical mediators of viral control with considerable potential to affect morbidity and mortality outcomes. They further suggest that both stimulatory and inhibitory NK receptor polymorphisms alter NK cell sensing of MHC I ligands on viral targets, which influences how NK cells respond to infection. In many cases, however, the underlying causes associated with host outcomes remain elusive. Herein, we discuss several modes of NK cell sensing of MHC I and MHC I-like molecules on viral targets, and the role of genetic diversity in this evolutionarily dynamic process. We further suggest that natural selection for paired NK receptors with opposing function, but shared MHC I ligands may give rise to rare, but highly effective MHC I-dependent modes of NK cell sensing of viral targets.