Toll-like Receptor 7 Is Required for Effective Adaptive Immune Responses that Prevent Persistent Virus Infection

Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses

“…TLR9/MyD88 signaling in DCs increased the magnitude of anti-NP IgG produced by promoting the expansion of T FH cells and GC B cells, whereas TLR9/MyD88 signaling in B cells primarily affected the quality of the GC response, resulting in better selection for high-affinity antibody, more class switching to IgG2a b , and a stronger secondary IgG response. Taken together, these data reveal that TLR9 signaling in multiple cell types cooperates to establish a coordinated GC reaction with characteristics previously demonstrated to be important in viral infection models, as well as in a mouse model of systemic lupus erythematosus (13,(41)(42)(43)(44).…”

“…Although a number of studies have indicated that TLRs promote rapid production of low-affinity Ig through extrafollicular antibody responses, several recent reports have shown that TLRs can also promote GC responses (5,(11)(12)(13)39). To analyze the mechanisms by which TLR signaling contributes to GC reactions, we turned to an oligovalent haptenated protein antigen (NP-CGG) conjugated with an oligonucleotide either containing or lacking CpG motifs.…”

“…Initially, it was proposed that TLR signaling selectively favored the extrafollicular component of serological immunity (10), but it was shown subsequently that TLR signaling in B cells could greatly augment the GC response to virus-like particles, nanoparticles, and virions (5,11,12). Moreover, the ability of B-cell TLRs to enhance the antibody response was recently shown to be important for host defense of mice infected with Friend virus and the chronic version of lymphocytic choriomeningitis virus (LCMV) (12)(13)(14).Follicular helper T (T FH ) cells maintain the GC and govern selection for GC B cells with increased affinity for antigen (8,15). The transcriptional repressor B-cell lymphoma-6 (Bcl-6) is essential for T FH cell development and for up-regulation of the chemokine receptor CXCR5, which promotes migration into B-cell follicles.…”

“…Initially, it was proposed that TLR signaling selectively favored the extrafollicular component of serological immunity (10), but it was shown subsequently that TLR signaling in B cells could greatly augment the GC response to virus-like particles, nanoparticles, and virions (5,11,12). Moreover, the ability of B-cell TLRs to enhance the antibody response was recently shown to be important for host defense of mice infected with Friend virus and the chronic version of lymphocytic choriomeningitis virus (LCMV) (12)(13)(14).…”

Type I interferon is a therapeutic target for virus-induced lethal vascular damage

“…Previous studies in C57BL/6 mice showed that induction of these cytokines by LCMV is mediated by viral RNA engagement of both endosomal Toll-like receptors (TLRs) and cytosolic RNA sensors (RIG-I and MDA5) (28)(29)(30)(31)(32). We found that congenic NZB mice lacking either expression of TLR3 (Tlr3 −/− ), or signaling by all endosomal TLRs (TLRs 3, 7, and 9) due to the 3d mutation of UNC93B1 (Unc93b1 3d/3d ) (33), succumbed to Cl13 infection unless treated with IFNAR-blocking antibody (Fig.…”