UC San Diego

Cardif, also known as IPS-1, VISA and, MAVS, is an intracellular adaptor protein that functions downstream of the RIG-I family of pattern recognition receptors. Cardif is required for the production of type I-IFNs and other inflammatory cytokines after RIG-I like receptors recognize intracellular antigenic RNA. Studies have recently shown that Cardif may have other roles in the immune system in addition to its role in viral immunity. In this study, we find that the absence of Cardif alters normal natural killer cell development and maturation. Cardif-/- mice have a 35% loss of mature CD27-CD11b⁺ NK cells in the periphery. Additionally, Cardif-/- NK cells have altered surface marker expression, lower cytotoxicity, decreased intracellular STAT1 levels, increased apoptosis and decreased proliferation compared to wild-type NK cells. Mixed chimeric mice revealed that the defective maturation and increased apoptotic rate of peripheral Cardif-/- NK cells is cell-intrinsic. Surprisingly, Cardif -/- mice showed enhanced control of mouse cytomegalovirus (MCMV, a DNA b-herpesvirus), commensurate with increased activation and IFN[Upsilon] production by these immature NK cell subsets. In addition, Cardif-/- mice have an increased Teff:Treg ratio and increased production of IFN[Upsilon] by CD8⁺ T cells. These results indicate that the skewed differentiation and altered STAT expression of Cardif-/- NK cells can result in their hyper- responsiveness in some settings, and support recent findings that Cardif-dependent signaling can regulate aspects of immune cell development and/or function distinct from its well characterized role in mediating cell-intrinsic defense to RNA viruses