Comparable T helper 1 (Th1) and CD8 T-cell immunity by targeting HIV gag p24 to CD8 dendritic cells within antibodies to Langerin, DEC205, and Clec9A

摘要

Improved protein-based vaccines should facilitate the goal of effective vaccines against HIV and other pathogens. With respect to T,cells, the efficiency of immunization, or "immunogenicity," is improved by targeting vaccine proteins to maturing dendritic cells (DCs) within mAbs to DC receptors. Here, we compared the capacity of Langerin/CD207, DEC205/CD205, and Clec9A receptors, each expressed on the CD8~+ DC subset in mice, to bring about immunization of microbial-specific T cells from the polyclonal repertoire, using HIV gag-p24 protein as an antigen. α-Langerin mAb targeted splenic CD8~+ DCs selectively in vivo, whereas α-DEC205 and α-Clec9A mAbs targeted additional cell types. When the mAb heavy chains were engineered to express gag-p24, the α-Langerin, α-DEC205, and a-Clec9A fusion mAbs given along with a maturation stimulus induced comparable levels of gag-specific T helper 1 (Th1) and CD8~+ T cells in BALB/c x C57BL/6 F1 mice. These immune T cells were more numerous than targeting the CD8~- DC subset with α-DCIR2-gag-p24. In an in vivo assay in which gag-primed T cells were used to report the early stages of T-cell responses, a-Langerin, α-DEC205, and a-Clec9A also mediated cross-presentation to primed CD8~+ T cells if, in parallel to antigen uptake, the DCs were stimulated with a-CD40. a-Langerin, ce-DEC205, and a-Clec9A targeting greatly enhanced T-cell immunization relative to non-binding control mAb or nontargeted HIV gag-p24 protein. Therefore, when the appropriate subset of DCs is targeted with a vaccine protein, several different receptors expressed by that subset are able to initiate combined Th1 and CD8~+ immunity.