Evolutionary struggles between NK cells and viruses

Abstract

Natural killer (NK) cells can participate in immune responses either directly or indirectly. In the absence of cognate recognition of virus-infected cells, bystander NK cells can respond to interferons and cytokines, such as interleukin-12 (IL-12) and IL-18, induced during viral infections, and respond by secreting interferon-γ, as well as other cytokines and chemokines. Alternatively, NK cells can directly interact with and kill virus-infected cells by the release of perforin and granzymes. NK-cell-mediated resistance to mouse cytomegalovirus (MCMV) is conferred by the activating, DAP12-associated Ly49H receptor in C57BL/6 mice, which binds the MCMV-encoded m157 glycoprotein on the surface of virus-infected cells. In certain other mouse strains, m157 binds to the inhibitory Ly49I receptor, thereby providing potential protection of the virus-infected cells from NK-cell attack. Recently, another activating NK-cell receptor, Ly49P, in the Ma/My mouse strain has been shown to recognize MCMV-infected cells that express H2-D^k. NK cells also provide resistance against mousepox virus in certain mouse strains, such as C57BL/6, and mousepox resistance has been mapped to the NK-cell complex (NKC) on mouse chromosome 6, which contains the Ly49 genes and other genes preferentially expressed by NK cells, including NKR-P1, CD94 and the NKG2 genes. Population-based studies in humans have implicated genes in the KIR family and MHC class I in resistance to progression to AIDS in HIV-infected individuals and in the resolution of hepatitis C virus infections. Further studies are needed to establish the molecular basis for these correlations. Viruses have evolved sophisticated mechanisms to evade recognition by NK cells. Both human and mouse cytomegalovirus have evolved several genes encoding proteins that interact with and degrade the protein ligands of the activating NKG2D receptors expressed by NK cells and T cells. Similarly, certain monkeypox and cowpox viruses have also evolved genes that encode soluble, secreted NKG2D antagonists, presumably to avoid detection by this receptor. Viral mimics of MHC class I molecules expressed by the cytomegaloviruses can function as agonists for the inhibitory receptors on NK cells. These observations indicate an evolutionary struggle between NK cells and viruses to allow preservation of both the host and the pathogen.