Contribution of Toll-like receptor signaling to germinal center antibody responses

Abstract

Toll-like receptors (TLRs) have emerged as one of the most important families of innate immune receptors for initiating inflammation and also for promoting adaptive immune responses. Recent studies have examined the ability of TLRs to promote antibody responses, including T-cell-dependent antibody responses. Initial study suggested that TLR stimulation promotes primarily an extrafollicular antibody response, which rapidly produces moderate affinity antibodies made by short-lived plasma cells. Recent studies, however, have shown that TLRs can also enhance the germinal center response, which produces high affinity class-switched antibody made by long-lived plasma cells. TLR stimulation can increase the magnitude of the latter response and also enhance selection for high affinity IgG. This review summarizes recent advances in understanding the roles of TLRs in B cells and also in other cell types for enhancement of antibody responses, with an emphasis on T-cell-dependent and germinal center antibody responses.

Fig. 1. TLRs enhance GC IgG responses in two distinct ways

1) TLRs of dendritic cells (DC) can detect TLR ligands such as CpG oligonucleotides either attached to antigens (shown) or simply mixed with them (not shown), and this recognition can enhance DC activation of CD4⁺ T cells, leading to a vigorous GC response. When the antigen in question is a soluble, low valency protein antigen-CpG conjugate, then recognition by B cell TLR9 does not enhance the IgG response. 2) In some circumstances, TLRs of B cells can promote a T-cell-dependent antibody response. This has been seen most prominently in the case of polyvalent antigens such as virus-like particles (VLPs). The exact mechanism is not established so the figure shows two possible mechanisms. 2a) Combined TLR and BCR signals may cause some antigen-specific B cells to choose a GC fate instead of an extrafollicular fate, which might otherwise be favored in the case of a polyvalent antigen that can induce robust BCR signaling. 2b) B cells at the GC stage may respond in a synergistic fashion to the combination of BCR and TLR stimulation to greatly enhance the magnitude of the GC IgG response. These two possible mechanisms are not mutually exclusive, and TLR signaling in B cells may contribute at both stages to the immune response. It should be noted that in the case of the response to a VLP antigen, the participation of dendritic cells is required but their TLRs do not boost the amount of antibody production. Finally, some types of antigens trigger TLRs in both dendritic cells and in B cells to promote the GC response, as in the case of some oligovalent haptenated protein antigens.

Fig. 1. TLRs enhance GC IgG responses in two distinct ways

1) TLRs of dendritic cells (DC) can detect TLR ligands such as CpG oligonucleotides either attached to antigens (shown) or simply mixed with them (not shown), and this recognition can enhance DC activation of CD4⁺ T cells, leading to a vigorous GC response. When the antigen in question is a soluble, low valency protein antigen-CpG conjugate, then recognition by B cell TLR9 does not enhance the IgG response. 2) In some circumstances, TLRs of B cells can promote a T-cell-dependent antibody response. This has been seen most prominently in the case of polyvalent antigens such as virus-like particles (VLPs). The exact mechanism is not established so the figure shows two possible mechanisms. 2a) Combined TLR and BCR signals may cause some antigen-specific B cells to choose a GC fate instead of an extrafollicular fate, which might otherwise be favored in the case of a polyvalent antigen that can induce robust BCR signaling. 2b) B cells at the GC stage may respond in a synergistic fashion to the combination of BCR and TLR stimulation to greatly enhance the magnitude of the GC IgG response. These two possible mechanisms are not mutually exclusive, and TLR signaling in B cells may contribute at both stages to the immune response. It should be noted that in the case of the response to a VLP antigen, the participation of dendritic cells is required but their TLRs do not boost the amount of antibody production. Finally, some types of antigens trigger TLRs in both dendritic cells and in B cells to promote the GC response, as in the case of some oligovalent haptenated protein antigens.