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.
Keywords: ANOVA, analysis of variance; AP, alkaline phosphatase; APC, antigen-presenting cells; CD, cluster of differentiation; CD40; CFSE, carboxyfluorescein succinimidyl ester; CTL, cytotoxic T lymphocyte; Coh, cohesin; Cross-presentation; DC, dendritic cell; Dendritic cell; Doc, dockerin; EEA1, early endosome antigen 1; ELISA, enzyme-linked immunosorbent assay; ELISpot, enzyme-linked immunospot; Flu.M1, influenza virus matrix protein 1; GM-CSF, granulocyte-macrophage colony-stimulating factor; HA1, hemagglutinin subunit 1; HLA, human leukocyte antigen; HPV, human papillomavirus; HRP, horseradish peroxidase; IFN, interferon; IL, interleukin; JaCoP, Just another Colocalization Plugin; LAMP-1, lysosomal-associated membrane protein 1; Lectins; MART-1, melanoma antigen recognized by T cells 1; MHC, major histocompatibility complex; Mo-DC, monocyte-derived dendritic cell; NHP, non-human primate; NP, nucleoprotein; PBMC, peripheral blood mononuclear cells; PBS, phosphate-buffered saline; PSA, prostate specific antigen; Poly(I:C), polyinosinic:polycytidylic acid; TLR, toll-like receptor; TMB, 3,3′,5,5′-tetramethylbenzidine; TNF, tumor necrosis factor; Vaccine; hCD40Tg, human CD40 transgenic; i.p., intraperitoneal(ly); mAb, monoclonal antibody; mDC, myeloid dendritic cell; pDC, plasmacytoid dendritic cell; s.c., subcutaneous(ly).