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

Abstract

Recent studies have demonstrated important roles of nucleic acidsensing Toll-like receptors (TLRs) in promoting protective antibody responses against several viruses. To dissect how recognition of nucleic acids by TLRs enhances germinal center (GC) responses, mice selectively deleted for myeloid differentiation primaryresponse protein 88 (MyD88) in B cells or dendritic cells (DCs) were immunized with a haptenated protein antigen bound to a TLR9 ligand. TLR9 signaling in DCs led to greater numbers of follicular helper T (T FH ) cells and GC B cells, and accelerated production of broad-affinity antihapten IgG. In addition to modulating GC selection by increasing inducible costimulator (ICOS) expression on T FH cells and reducing the number of follicular regulatory T cells, MyD88-dependent signaling in B cells enhanced GC output by augmenting a class switch to IgG2a, affinity maturation, and the memory antibody response. Thus, attachment of a TLR9 ligand to an oligovalent antigen acted on DCs and B cells to coordinate changes in the T-cell compartment and also promoted B cell-intrinsic effects that ultimately programmed a more potent GC response.T he ability of the innate immune system to survey infection relies on pattern recognition receptors, such as Toll-like receptors (TLRs), that signal through myeloid differentiation primary-response protein 88 (MyD88) upon recognition of pathogen-associated molecular patterns (PAMPs). Recognition of infection by TLRs shapes adaptive immunity by directing dendritic cells (DCs) to activate naive T cells (1-3), by directing T helper (T H ) 1 and T H 17 polarization of effector T cells (3, 4), and by promoting B-cell activation and terminal differentiation to antibody-secreting plasma cells (5, 6).Following infection or vaccination, antibody responses generally proceed in two phases: an initial extrafollicular response, which rapidly generates short-lived plasmablasts that secrete low-affinity IgM and small quantities of isotype-switched antibodies (7), and a slower germinal center (GC) response, where B cells switch Ig isotype, increase affinity for antigen through somatic mutation of IgH and IgL genes, and undergo selection processes (8). Importantly, the GC builds protection from reinfection by selecting long-lived plasma cells and memory B cells from cells expressing isotype-switched, affinity-matured Bcell antigen receptors (BCRs) (9). 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 (...

A critical role of T follicular helper cells in human mucosal anti-influenza response that can be enhanced by immunological adjuvant CpG-DNA

“…These results are concordant with the recent reports in mouse models that CpG-DNA could increase T FH and B cell responses (Chakarov and Fazilleau, 2014;Mastelic et al, 2012;Rookhuizen and DeFranco, 2014).…”

Oil-in-Water Emulsion MF59 Increases Germinal Center B Cell Differentiation and Persistence in Response to Vaccination

“…Previous publications have reported a correlation between the magnitude of GC B cells and T FH cells in response to increasing amount of Ag or to TLR agonists in the adjuvant formulation (39,42,43); in addition, a recent study from Siegrist and colleagues (44) has shown that MF59 promotes potent T FH and GC B cell responses in adult mice, whereas younger infant mice, which develop only few functional T FH cells, have poor GC and Ab responses. In the present work, we show higher frequencies of T FH cells in proximal-draining LNs of mice that received the MF59 formulation compared with the alum group, hence confirming the importance of the adjuvant in shaping T FH cell responses and providing a possible explanation to the sustained Ag-specific GC B cell responses observed with MF59 formulation.…”

The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6

“…Along this line, Karnowski et al (2012) have recently reported that Pou2af1 −/− CD4 + T cells are not impaired in their ability to differentiate into Tfh cells during influenza infection in mice reconstituted with wild‐type B cells. Viral infections, however, elicit strong Toll‐like receptor signals not only in DCs and B cells, but also in CD4 + T cells that, depending on the pathogenic stimulus and the anatomic compartment, promote the generation of Tfh cells and adaptive immune responses (Hou et al , 2011; Rookhuizen & Defranco, 2014; Kubinak et al , 2015). Based on our observation that Bob can be decisive for CD4 + T‐cell differentiation (Brunner et al , 2007), we analyzed Pou2af1 +/+ : Pou2af1 −/− mixed bone marrow chimeras to determine whether the effects of Bob1‐deficiency on Tfh cell differentiation are CD4 + T cell‐intrinsic or secondary to defects in the B‐cell compartment of Pou2af1 −/− mice.…”