Toll‐like receptor 4 signalling regulates antibody response to adenoviral vector‐based vaccines by imprinting germinal centre quality

Abstract

Adenoviral vectors (AdV) are considered promising candidates for vaccine applications. A prominent group of Toll-like receptors (TLRs) participate in the adenovirus-induced adaptive immune response, yet there is little information regarding the role of TLR4 in AdV-induced immune responses in recent literature. We investigated the function of TLR4 in both adaptive and innate immune responses to an AdV-based anthrax vaccine. By immunizing wild-type and TLR4 knockout (TLR4-KO) mice, we revealed the requirement of TLR4 in AdV-induced innate responses. We also showed that TLR4 functions are required for germinal centre responses in immunized mice, as expression of the apoptosis-related marker Fas was down-regulated on germinal centre B cells from TLR4-KO mice. Likewise, decreased expression of inducible costimulator on follicular T helper cells was observed in immunized TLR4-KO mice. Moreover, a potent protective antigen-specific humoral immune response was mimicked using an adjuvant system containing the TLR4 agonist monophosphoryl lipid A. Overall, our findings showed that very rapid antigen-specific antibody production is correlated with the TLR4-imprinted germinal centre response to AdV-based vaccine. These results provide additional evidence for the use of the AdV and a TLR agonist to induce humoral responses. Our findings offer new insights into rational vaccine design.

Effects of low molecular weight peptides from monkfish (Lophius litulon) roe on immune response in immunosuppressed mice

“…When TLRs recognize relevant molecules, they activate downstream regulatory molecules such as NF-κB or interferon regulatory factor (IRF) to conduct immune signal transduction and induce and stimulate cells to produce effector molecules to kill foreign pathogens ( 13 ). TLR 4 is an important part of the TLRs family ( 42 , 43 ). Numerous studies found that TLR 4 recognizes peptides and activates the downstream regulatory signal pathways, such as NF-κB and MAPK, to exert immunomodulatory effects ( 44 , 45 ).…”

Pathogenesis of vaccine-induced immune thrombotic thrombocytopenia (VITT)

“…The proinflammatory signal clinically manifests as typical reactions towards vaccination within the first 24 to 48 hours, which include fever, chills, and headache. These acute reactions are likely induced by proteins in the vaccine, especially the non-assembled hexon proteins (see above), which can bind to innate immune cell receptors [39] , inducing inflammation.…”

Adenovirus vector and mRNA vaccines: Mechanisms regulating their immunogenicity

“…In contrast, interferon signaling to both B cells and CD4 + T cells was required for optimal production of IgG. Another study examining the impact of TLR4 deficiency on Ad5‐induced humoral immune responses also identified impaired GC responses, lower transgene‐specific IgG titers, and impaired CD4 + T cell responses [ 116 ]. Whether this shared phenotype reflects a common pathway around impaired induction of type I interferon in the absence of TLR4 signaling was not explored.…”