these cytokines actually inhibit host defense against L. monocy- togenes infection. Compared with wild-type mice, IRF3- and IFNAR1-deficient animals have a greatly improved ability to control the bacterial challenge. Furthermore, exogenous de- livery of the type I IFN–inducing agent poly I:C dramatically sensitized mice to L. monocytogenes inoculation in an IFNAR1-dependent manner. These studies indicate that L. monocytogenes benefits from the cellular programming medi- ated by type I IFNs. Although the complete mechanism by which type I IFNs inhibit host immunity to L. monocytogenes is likely complex due to the pleiotropic cellular effects medi- ated by these cytokines (2), our findings suggest that IRF3- and IFNAR1-deficient mice might be more resistant to L. monocytogenes infection because their splenocytes do not suc- cumb to type I IFN–mediated apoptosis. We observed massive apoptosis in lymphocyte-rich folli- cles in the spleens of L. monocytogenes–infected wild-type mice by 2 d after infection. Previous reports have found similar patterns of apoptosis clearly involving uninfected T 443 O’Connell et al. Figure 5. L. monocytogenes–induced splenic apoptosis is dependent on type I IFNs. (A) Spleens from IFNAR1 / , IRF3 / , and wild-type mice that had been infected with 1.5 106 L. monocytogenes 48 h previously were removed and subjected to a TUNEL assay followed by DAPI stain- ing of the nuclei. Pictures were taken using a 10 lens. (B) Portions of the spleens from wild-type (n 3), IRF3 / (n 3), and IFNAR1 / (n 4) mice used for TUNEL assays in A were assayed and presented as CFUs 2 d after infection with 1.5 106 L. monocytogenes. All data repre- sent three independent experiments. and B lymphocytes, and potentially other cell types, within close proximity to L. monocytogenes–laden macrophages (29). These findings suggest that one or more autocrine/ paracrine factors produced by the infected macrophages in- duce apoptosis in neighboring cells and possibly macro- phages themselves. However, blocking such known media- tors of apoptosis as TNF, IL-1, IFN- , and nitric oxide had no effect on the apoptotic lesion (29). In our study, we found greatly reduced numbers of TUNEL cells in the spleens of mice deficient in either IRF3 or IFNAR1 com- pared with wild-type spleens despite the presence of similar bacterial loads by 2 d after infection. Thus, type I IFNs are likely the paracrine factors responsible for the splenic apop- tosis observed in L. monocytogenes–infected mice. Although splenic T and B lymphocytes are clearly being killed by L. monocytogenes, Jiang et al. (30) have suggested that nonspecific, but not antigen-specific, T cells are tar- geted for deletion in this situation. However, experiments using SCID mice have indicated that B and T cells do not