Abstract
Dendritic cells (DC) and natural killer (NK) cells are critical components of the innate immune response to infection. Conditions marked by the absence of these cells result in rampant viral infections and immune pathologies. As first-line sensors and effectors, they are prime targets of immune-evasion by a multitude of viruses, including cytomegalovirus (CMV), measles virus (MV), lymphocytic choriomeningitis virus(LCMV), herpes simplex virus (HSV), Rauscher leukemia virus (RLV), Epstein-Barr virus (EBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) In particular, murine CMV is known to induce a drastic loss of DC in the spleen during acute infection. In mice, the MHC class I haplotype H-2k is historically associated with improved MCMV control. Mice of this genetic background exhibit reduced levels of viral replication compared to other strains. Our lab identified the H-2Dk molecule (Dk) as an essential factor in this model of genetic viral control. Subsequently, we also uncovered a crucial role for NK cells expressing the inhibitory receptor Ly49G2 in mediating this Dk-dependent control. Dk is a cognate ligand for Ly49G2 and is capable of educating NK cells expressing this inhibitory receptor – licensing them for enhanced sensitivity to activation signals and heightened effector functions (i.e. cytokine production and cytolysis). Ly49G2+ NK cells (G2+ NK) are capable of specifically detecting MCMV infection, but the mechanism of recognition is still the subject of ongoing work. However, these cells are critical to viral control since specific depletion of this subset results in virus levels comparable to mice lacking efficient MCMV control. Using this model, we have explored the ability of MCMV to dysregulate DC dynamics during infection and the ability of these virus-responsive, licensed NK cells to counter this process. Type I IFN (IFN-I) has been regarded as a prime candidate for inducing dendritic cell toxicity during acute MCMV infection. However, upon rigorously exploring this phenomenon, we observed the majority of DC loss during MCMV infection occurred independently of IFN-I signaling. Interestingly, sensitivity to IFN-I-induced loss appears to vary between different subsets of splenic DC. We have also further explored the IFN-independent mechanism of DC loss, investigating IL-6, soluble serum factors, cell death pathways, and cell trafficking. To date, we have not been able to conclusively determine the source of DC attrition, but work is ongoing. Whatever the mechanism, it is clear that virus-responsive NK cells play a critical role in reversing the DC loss. Mice that control MCMV via G2+ NK rapidly recover their DC populations and display enhanced DC numbers following recovery. This effect is dependent on G2+ NK and their ability to efficiently recognize MCMV infection. Hence, we have investigated, for the first time, mechanisms of MCMV-induced DC loss in an MHC-dependent model of viral control and the role of MHC class I-licensed NK cells in countering this form of immunosuppression.
