IL-10 is an anti-inflammatory cytokine that regulates the extent of host immunity to infection by exerting suppressive effects on different cell types. Herpes viruses induce IL-10 to modulate the virus-host balance towards their own benefit, resulting in prolonged virus persistence. To define the cellular and molecular players involved in IL-10 modulation of herpes virus-specific immunity, we studied mouse cytomegalovirus (MCMV) infection. Here we demonstrate that IL-10 specifically curtails the MCMV-specific CD4 T cell response by suppressing the bidirectional crosstalk between NK cells and myeloid dendritic cells (DCs). In absence of IL-10, NK cells licensed DCs to effectively prime MCMV-specific CD4 T cells and we defined the pro-inflammatory cytokines IL-12, IFN-γ and TNF-α as well as NK cell activating receptors NKG2D and NCR-1 to regulate this bidirectional NK/DC interplay. Consequently, markedly enhanced priming of MCMV-specific CD4 T cells in Il10-/-mice led to faster control of lytic viral replication, but this came at the expense of TNF-α mediated immunopathology. Taken together, our data show that early induction of IL-10 during MCMV infection critically regulates the strength of the innate-adaptive immune cell crosstalk, thereby impacting beneficially on the ensuing virus-host balance for both the virus and the host.

dx.doi.org/10.1371/journal.ppat.1002846, hdl.handle.net/1765/37825
PL o S Pathogens (Online)
Erasmus MC: University Medical Center Rotterdam

Mandaric, S, Walton, S.M, Rülicke, T, Richter, K, Girard-Madoux, M.J.H, Clausen, B.E, … Oxenius, A. (2012). IL-10 Suppression of NK/DC Crosstalk Leads to Poor Priming of MCMV-Specific CD4 T Cells and Prolonged MCMV Persistence. PL o S Pathogens (Online), 8(8). doi:10.1371/journal.ppat.1002846