Functional Specialty of CD40 and Dendritic Cell Surface Lectins for Exogenous Antigen Presentation to CD8+ and CD4+ T Cells

• Antigen delivery to DCs via CD40 is more efficient than through nine other receptors at eliciting CD8 T+ cell response.
• Antigen delivery via lectins (e.g., LOX-1 and Dectin-1) is more efficient than CD40 at eliciting CD4+ T cell responses.The success of an immunotherapeutic vaccine for cancer is largely dependent on its ability to evoke potent cellular immunity. Although targeting antigens to dendritic cells (DCs) has been known to be an efficient strategy to evoke cellular immunity, which targeted receptors yield the optimal cellular immunity remained elusive. We report that targeting CD40, compared to 9 other DC receptors, results in the greatest levels of CD8+ cytotoxic T cell responses, while targeting lectins results in enhanced CD4+ helper T cell responses. The findings of this study will assist us in the rational design of immunotherapeutic vaccines against cancers.

Dendritic cells (DCs) are major antigen-presenting cells that can efficiently prime and cross-prime antigen-specific T cells. Delivering antigen to DCs via surface receptors is thus an appealing strategy to evoke cellular immunity. Nonetheless, which DC surface receptor to target to yield the optimal CD8+ and CD4+ T cell responses remains elusive. Herein, we report the superiority of CD40 over 9 different lectins and scavenger receptors at evoking antigen-specific CD8+ T cell responses. However, lectins (e.g., LOX-1 and Dectin-1) were more efficient than CD40 at eliciting CD4+ T cell responses. Common and distinct patterns of subcellular and intracellular localization of receptor-bound αCD40, αLOX-1 and αDectin-1 further support their functional specialization at enhancing antigen presentation to either CD8+ or CD4+ T cells. Lastly, we demonstrate that antigen targeting to CD40 can evoke potent antigen-specific CD8+ T cell responses in human CD40 transgenic mice. This study provides fundamental information for the rational design of vaccines against cancers and viral infections.