Lymphotoxin-Mediated Crosstalk between B Cells and Splenic Stroma Promotes the Initial Type I Interferon Response to Cytomegalovirus

SummaryToll-like receptor (TLR)-dependent pathways control the production of IFNαβ, a key cytokine in innate immune control of viruses including mouse cytomegalovirus (MCMV). The lymphotoxin (LT) αβ-LTβ receptor signaling pathway is also critical for defense against MCMV and thought to aid in the IFNβ response. We find that upon MCMV infection, mice deficient for lymphotoxin (LT)αβ signaling cannot mount the initial part of a biphasic IFNαβ response, but show normal levels of IFNαβ during the sustained phase of infection. Significantly, the LTαβ-dependent, IFNαβ response is independent of TLR signaling. B, but not T, cells expressing LTβ are essential for promoting the initial IFNαβ response. LTβR expression is required strictly in splenic stromal cells for initial IFNαβ production to MCMV and is dependent upon the NF-κB-inducing kinase (NIK). These results reveal a TLR-independent innate host defense strategy directed by B cells in communication with stromal cells via the LTαβ cytokine system.