Abstract
Despite recent advances in developing and licensing adjuvants, there is a great need for more potent formulations to enhance immunogenicity of vaccines. An Eimeria tenella derived antigen (rEA) augments immune responses against several pathogens in animal models and recently was confirmed to be safe for human use. In this study, we have analyzed the molecular mechanisms underlying rEA activity in mice, and confirmed that rEA activates multiple immune cell types, including DCs, macrophages, NK, B, and T cells. The rEA adjuvant also elicits the induction of pleiotropic pro-inflammatory cytokines, responses that completely depend upon the presence of the TLR adaptor protein MyD88. Surprisingly, we also found that the TRIF adaptor protein acts as a potent negative regulator of TLR agonist-triggered immune responses. For example, IL12 production and the induction of co-stimulatory molecule expression by DCs and IFNγ production by NK cells in vivo were significantly increased in rEA-treated TRIF-KO mice. Importantly, however, TRIF suppressive effects were not restricted to rEA-mediated responses, but were apparent in LPS- or ODN2006-activated DCs as well. Taken together, our findings confirm that rEA is a potent adjuvant, triggering robust activation of the innate immune system, in a manner that is augmented by MyD88 and inhibited by TRIF; thereby unveiling the potential complexities of modulating TLR activity to augment vaccine efficacy.
Highlights
There is a great need to develop more efficient vaccines to combat or prevent infections by a number of detrimental pathogens that continue to plague mankind [1,2,3]
TRIF acts as a negative regulator of rEA-induced MyD88-dependent activation of dendritic cells and macrophages in vivo
We found significant increases in the percent of CD40+, CD80+ and CD86+ dendritic cells (DCs) in rEA treated wild type (WT) mice, but no such increases were observed in rEA treated MyD88 knockout (KO) or MyD88/TRIF double knockout (DKO) mice, each as compared to mock-injected animals (Figures 1, 2 and Figures S1, S2)
Summary
There is a great need to develop more efficient vaccines to combat or prevent infections by a number of detrimental pathogens that continue to plague mankind [1,2,3]. The use of novel adjuvants capable of beneficially stimulating the immune system to maximize efficacy of various vaccination strategies is a rapidly developing field. Most adjuvants augment the induction of innate immune responses by triggering robust activation of dendritic cells (DCs) and macrophages, actions that can result in improved induction of antigen specific adaptive immune responses. Incorporation of Toll-like receptor (TLR) ligands into vaccine formulations represent a class of adjuvants proposed for usage in generation vaccines. This is primarily due to TLRs being expressed at high levels on important immune cell types (DCs, macrophages, NK cells) and their ability to potently activate the innate immune system [4,5,6]
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