| Innate cytokine responses to acute infections with lymphocytic choriomeningitis virus (LCMV) include the robust and sustained induction of the type 1 interferons (IFN). This Ph.D. thesis examines the cellular sources, architectural conditions, and signaling pathways by which these cytokines are produced in the spleen. Experiments evaluating the requirements for an IFN response to LCMV resulted in the surprising discovery that mice deficient in B and T cell development had profoundly reduced levels of IFN in serum and spleen, despite high viral replication. In addition to lacking an adaptive immune system, these strains exhibit aberrant splenic architecture, and the defect in IFN production was also observed in mice lacking normal splenic marginal zone (MZ) organization due to genetic deficiencies in B cells or cytokine functions required for development of the MZ. Depletion of phagocytic cells from normally-developed spleens demonstrated that these populations were required for the IFN response to LCMV and for control of viral replication. Complete repopulation of the MZ, taking more than two months, was necessary to restore normal IFN production. In contrast, control of LCMV replication occurred two weeks following depletion and correlated with the return of CD11c+ cells. Under normal conditions, plasmacytoid dendritic cells were not necessary for the IFN response against LCMV in 129 mice. Interestingly, however, they did contribute in BL/6 mice but were not the sole producers during infection. Enrichment of myeloid dendritic cells and surprisingly, marginal zone macrophages, showed that these populations were also producing IFN during LCMV infection. Toll-like receptor (TLR) signaling (as indicated by mice deficient in MyD88, TLR2, TLR3, and TLR4) and the dsRNA-dependent protein kinase PKR were not required for the peak IFN response. Taken together, the work performed herein demonstrates that production of type 1 IFN against LCMV is a complex process involving strict architectural requirements, several producing cell types, and a still unknown signaling mechanism for induction. These results significantly advance our understanding of the role for lymphoid tissue architecture in establishing the host-pathogen relationship and early innate responses. Moreover, they extend our knowledge about conditions that support production of type 1 IFN by specialized cell types. |
