The PYHIN protein family as mediators of host defenses. the activation of natural killer (NK) cells, which produce gamma interferon in an IFN-I-dependent fashion, and is impartial of Ly49H. Strikingly, MCMV production in the spleens of immunocompetent mice never increases at times after 32 h. These results highlight the crucial importance of lymphoid-tissue stromal cells in orchestrating the earliest phase of innate defense to MCMV contamination, capping replication levels, and blocking spread until contamination is usually ultimately controlled. INTRODUCTION Cytomegalovirus (CMV; a betaherpesvirus) infects the majority of the world’s populace (1). Main CMV contamination is usually asymptomatic in healthy individuals; however, in persons with suppressed or underdeveloped immunity, it can result in serious disease (2). Upon immune suppression, CMV reactivates rapidly from latency, demonstrating the need for constant immune surveillance to maintain homeostasis between CMV and its host over this lifetime infection. The complexity of this intricate relationship between CMV and its host makes it ideal for use in case studies of how host immunity controls the various phases of acute, prolonged, and latent contamination (3C5). Because CMV replication is usually species restricted, readily tractable animal models for studying human CMV (HCMV) contamination are unavailable, and mouse CMV (MCMV; a natural mouse pathogen) has provided invaluable insight into the mechanisms required for both innate and adaptive immune control of CMV contamination. Type I interferon (IFN-I) and natural killer (NK) cells are key components of innate defense against infections with most viruses, including MCMV (6). High systemic IFN-I levels are detectable as early as 6 h after MCMV contamination (7), peaking at 8 to 12 h (8). A second wave of systemic and splenic IFN-I occurs at 36 to 48 h. At 36 h, the majority of this IFN-I is usually produced by plasmacytoid dendritic cells (pDCs) in a Toll-like receptor (TLR)- and MyD88-dependent manner (9C14), and this level of production occurs almost simultaneously with completion of the first round of MCMV replication in the spleen (8). Slightly later (44 to 48 h), the bulk of IFN-I is produced by standard DCs (cDCs) in a MyD88-impartial fashion. This composite, second wave of the innate response occurring at 36 to 48 h is critical for efficient NK cell activation and restriction of MCMV replication at days 2 to 3 3 of contamination. MyD88- and TLR9-deficient (MyD88?/? and TLR9?/?) mice exhibit severely reduced levels of systemic IFN-I, interleukin-12 (IL-12), and gamma interferon (IFN-) at 36 h and enhanced MCMV replication at 72 to 96 h (11, 12, 14C16), due, at least in large part, to defective cytokine-mediated Anavex2-73 HCl NK cell activation (10, 17C21). IL-12 activates NK cells in a signal transducer and activation of transcription 4 (STAT4)-dependent manner, resulting in their production of IFN- (10, 18C20, 22). Commensurately, IFN-I induces the proliferation and cytotoxicity of NK cells during MCMV contamination through the regulation of STAT1 and IL-15 (18, 19, 23). Notably, MCMV contamination actually promotes a loss of total Anavex2-73 HCl splenic NK cells during the first 2 days, with a subsequent growth/activation of Ly49H-positive (Ly49H+) NK cells in C57BL/6 (B6) mice occurring at time points after day 2 Anavex2-73 HCl through acknowledgement of the viral m157 protein (24C28). Previous work Anavex2-73 HCl has shown that innate defenses regulated by lymphotoxin (LT)-LT receptor (LTR) signaling are important for early control of MCMV (29C31). The initial systemic and splenic IFN-I that peaks at 8 to 12 h after MCMV contamination is produced by splenic stromal cells that express CAB39L LTR and requires B cells that express LT (8, 32). This innate defense mediated by LT-expressing B cells is not unique to stromal cells, as cross talk between B cells and LTR-expressing subcapsular sinus macrophages has recently been shown to regulate IFN-I production in the lymph node during vesicular stomatitis computer virus (VSV) contamination (33, 34). Recently, marginal-zone (MZ) stromal cells have been shown to be the first cells infected by MCMV in the spleen (35), and.