Toll-Like Receptor Ligand-Based Vaccine Adjuvants Require Intact MyD88 Signaling in Antigen-Presenting Cells for Germinal Center Formation and Antibody Production.

Lee M. Wetzler,Michael L. Reiser,Munir M. Mosaheb

doi:10.3389/fimmu.2017.00225

Lee M. Wetzler, Michael L. Reiser + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2017.00225

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Abstract

Vaccines are critical in the fight against infectious diseases, and immune-stimulating adjuvants are essential for enhancing vaccine efficacy. However, the precise mechanisms of action of most adjuvants are unknown. There is an urgent need for customized and adjuvant formulated vaccines against immune evading pathogens that remain a risk today. Understanding the specific role of various cell types in adjuvant-induced protective immune responses is vital for an effective vaccine design. We have investigated the role of cell-specific MyD88 signaling in vaccine adjuvant activity in vivo, using Neisserial porin B (PorB), a TLR2 ligand-based adjuvant, compared with an endosomal TLR9 ligand (CpG) and toll-like receptor (TLR)-independent (alum, MF59) adjuvants. We found that intact MyD88 signaling is essential, separately, in all three antigen-presenting cell types [B cells, macrophages, and dendritic cells (DCs)] for optimal TLR ligand-based adjuvant activity. The role of MyD88 signaling in B cell and DC in vaccine adjuvant has been previously investigated. In this study, we now demonstrate that the immune response was also reduced in mice with macrophage-specific MyD88 deletion (Mac-MyD88−/−). We demonstrate that TLR-dependent adjuvants are potent inducers of germinal center (GC) responses, but GCs are nearly absent in Mac-MyD88−/− mice following immunization with TLR-dependent adjuvants PorB or CpG, but not with TLR-independent adjuvants MF59 or alum. Our findings reveal a unique and here-to-for unrecognized importance of intact MyD88 signaling in macrophages, to allow for a robust vaccine-induced immune responses when TLR ligand-based adjuvants are used.

Highlights

Immune adjuvants are necessary in most, if not all, vaccines, to enhance efficacy by increasing the immunogenicity of poorly immunogenic antigens
We examined the effect of deficient MyD88 signaling, separately, in each antigen-presenting cells (APCs) type, in regard to the adjuvant activity of porin B (PorB) and compared with an endosomal TLR9 ligand (CpG) as TLR2 and TLR9 ligand-based adjuvants, respectively
We provide detailed insight into the in vivo role of toll-like receptor (TLR) signaling through MyD88 in B cells, dendritic cells (DCs), or macrophages for TLR ligand-based vaccine adjuvant activity

Summary

INTRODUCTION

Immune adjuvants are necessary in most, if not all, vaccines, to enhance efficacy by increasing the immunogenicity of poorly immunogenic antigens. Intact TLR-MyD88 signaling in B cells and DCs has previously been shown to be important for induction of robust GCs and antibody production upon stimulation with TLR ligand-based adjuvants [25]. The impact of in vivo MyD88 signaling in specific immune cells, e.g., B cells, DCs, or macrophages, on TLR ligand-based immunomodulation, and subsequent vaccine efficacy was examined in this study. We used the loxP/cre recombinase system to conditionally knock out MyD88 in individual APC types in vivo Immunizations of these mice revealed the importance of functional cell-specific MyD88 signaling in the adjuvanticity of TLR-dependent and -independent adjuvants. Our findings confirm the importance of intact in vivo MyD88 signaling in B cells and DCs and reveal a here-to-for unrecognized importance in macrophages, demonstrating its contribution to a robust vaccineinduced immune response, including GC formation, when TLR ligands are used as adjuvants.

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ETHICS STATEMENT