Abstract
The toll-like receptor 9 (TLR9) agonists CpG oligodeoxynucleotides (CpG ODNs) have been recognized as promising adjuvants for vaccines against infectious diseases and cancer. However, the role of TLR9 signaling in the regulation of antigen uptake and presentation is not well understood. Therefore, to investigate the effects of TLR9 signaling, this study used synthetic peptides (IDG) and lipopeptides (lipoIDG), which are internalized by dendritic cells (DCs) via endocytosis-dependent and endocytosis-independent pathways, respectively. Our data demonstrated that the internalization of lipoIDG and IDG by bone marrow-derived dendritic cells (BMDCs) was not enhanced in the presence of CpG ODNs; however, CpG ODNs prolonged the co-localization of IDG with CpG ODNs in early endosomes. Surprisingly, CpG ODNs enhanced CD8+ T cell responses, and the anti-tumor effects of IDG immunization were stronger than those of lipoIDG immunization. LipoIDG admixed with CpG ODNs induced low levels of CD8+ T cells and partially inhibit tumor growth. Our findings suggest that CpG ODNs increase the retention of antigens in early endosomes, which is important for eliciting anti-tumor immunity. These results will facilitate the application of CpG adjuvants in the design of different vaccines.
Highlights
Aluminum salts is their inability to elicit CTL responses[8], which is an important protective mechanism against microbial infections and tumors
We found that fluorescein isothiocyanate (FITC)-conjugated RAH could not be internalized in bone marrow-derived dendritic cells (BMDCs) even in the presence of CpG ODNs
We found that intracellular IDG, but not lipoIDG, efficiently colocalized with CpG ODNs in both wild-type (WT) and TLR9 knockout (KO) BMDCs (Fig. 2A)
Summary
Aluminum salts is their inability to elicit CTL responses[8], which is an important protective mechanism against microbial infections and tumors. CpG ODNs were subsequently administered following the administration of antigen; antigen-specific immune responses were not enhanced[18] This finding led many studies to focus on the co-delivery of antigen and CpG ODNs to antigen-presenting cells (APCs) for the induction of cellular immunity. The cross-presentation of exogenous antigens by DCs is regulated by the engagement of TLRs and cytokines[25]; it remains unclear whether the co-administration of different types of antigens with TLR ligands can increase the antigen uptake ability or antigen presentation efficiency of DCs. In contrast, synthetic cationic peptides modulate the uptake of CpG ODNs, which enhances their immunostimulatory effects[26,27]. These findings suggest that CpG ODNs may enhance anti-tumor immunity via different mechanisms
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