Cytomegalovirus limits formation of intrahepatic myeloid-cell aggregates for T-cell population expansion by activating both MAPKAP kinases 2 and 3

Cytomegalovirus (CMV) circumvents sterile immunity and establishes a state of latency from which the virus reactivates under immunosuppressive conditions causing substantial morbidity and mortality. In the liver, which represents a prime site of CMV replication and latency, it can be causative for hepatitis when hosts are immunocompromised. We could recently demonstrate that an acute infection with murine (M)CMV induces activation of the MAP kinase activated protein kinase (MK)2, which is critical for the generation of a cytokine response to MCMV and drives an IFNAR1-dependent circuit that controls IL-10 production and limits aggregation of CD11b+ myeloid cells and proliferating CD8+ T-cells in the liver. These immune-cell aggregates resemble the so termed “intrahepatic myeloid-cell aggregates for T-cell population expansion (iMATE)”. iMATEs are predicted to enable a local accumulation and expansion of cytotoxic CD8+ T-cells without causing severe liver pathology. Understanding the mechanisms that control iMATE formation aims to develop strategies for their reactivation even under immunosuppressive conditions or during chronic infections that are usually accomponied by an exhaustion of CD8+ T-cells. The data presented in this study suggest that beside MK2 its homologue kinase MK3 is likewise involved in the control of MCMV-induced cytokine and chemokine release and in the regulation of iMATE formation, which is enhanced not only in the MK2-deficient (MK2-/-) liver, but also in the MK2/3-double-deficient (MK2/3-/-) liver. Furthermore, as viral replication in the liver of MK2-/- animals is not significantly affected, it is an interesting observation that viral replication is strongly diminished in the livers of MK2/3-/- animals. This indicates that the interplay of both MK2 and MK3 control a molecular and cellular evironment within the liver that facilitates viral replication and inhibits iMATE formation upon acute MCMV infection. Therefore, it is conceivable that viruses such as CMV exploit MK2- and/or MK2/3-dependent mechanisms to avoid iMATE formation and that this is part of a program involved in immune escape and possibly also establishment of latency.