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

Abstract

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 α-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 × 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, α-Langerin, α-DEC205, and α-Clec9A also mediated cross-presentation to primed CD8 + T cells if, in parallel to antigen uptake, the DCs were stimulated with α-CD40. α-Langerin, α-DEC205, and α-Clec9A targeting greatly enhanced T-cell immunization relative to nonbinding 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.antigen presentation | C-type lectins | cross-priming A major goal in the development of effective vaccines against pathogens such as HIV and malaria is the induction of durable and protective T-cell immunity. Attenuated viral vectors are being emphasized widely as a vaccine platform to elicit T-cell immunity in humans (1). Attenuated vectors have potential limitations with respect to immunogenicity and repeated use, however (2). Protein vaccines could provide a stand-alone or complementary platform (e.g., to viral vectors), with relative ease of production and ability to be repeatedly injected. Proteins are poorly immunogenic for T cells, however, even when administered repeatedly in high doses.Recent progress in immunobiology provides the potential to overcome this obstacle. The immunogenicity of proteins can be greatly enhanced by improving the delivery of protein to dendritic cells (DCs). To do this, one approach is to introduce the protein into mAbs that efficiently and specifically target to DC receptors in situ, within lymphoid tissues, and then to coadminister the fusion antibody with an appropriate agonist for DC maturation [reviewed in (3, 4)]. Delivery of vaccine proteins within mAbs increases the efficiency of antigen presentation on MHC class I and II molecules ∼100-fold and allows protein vaccines to induce T helper 1 (Th1) type CD4 + T cells and CD8 + T cells (5-8).The DC ...

The equivalents of human blood and spleen dendritic cell subtypes can be generated in vitro from human CD34+ stem cells in the presence of fms-like tyrosine kinase 3 ligand and thrombopoietin

“…5,39,[43][44][45] Such properties of this subset have been exploited in in vivo targeting experiments whereby antigens specifically targeted to the CD8 1 DC subset boost immune responses and shows promise in improving vaccine delivery and efficacy. 16,19,46 The generation of large numbers of DC subset equivalents in vitro from bone marrow precursors in the presence of Flt3L has facilitated further study of mouse DC subsets. 7 Recent studies in human blood and spleen have revealed the presence of a number of subsets 12,24 that are similar to those found in the mouse with respect to surface phenotype, TLR expression, transcription factor expression and overall transcriptional profile.…”

Criteria for Dendritic Cell Receptor Selection for Efficient Antibody-Targeted Vaccination

“…In the present study, we have solely relied on the use of OVA as a source of Ag for presentation. Ags other than OVA are presented following receptor targeting including HIV Gag (8,42,43) and human epidermal growth factor receptor 2 (44,45), highlighting the usefulness of Ab-targeted vaccination in settings of infection and cancer immunotherapy, respectively. We propose that findings identified in the present study are relevant to any Ag that is internalized via a specific receptor.…”

“…Specific trafficking routes that initiate more efficient MHC I or MHC II Ag presentation have not been strictly defined. For example, DEC205 (CD205), a molecule that traffics to late endosomes (4)(5)(6), is considered a superior receptor for MHC I cross-presentation (7)(8)(9)(10). Alternatively, MHC I cross-presentation is efficiently enhanced by receptors that traffic to early, but not late, endosomes (5,6,11,12).…”

Invariant NKT Cells Induce Plasmacytoid Dendritic Cell (DC) Cross-Talk with Conventional DCs for Efficient Memory CD8+ T Cell Induction

“…In the steady state, iNKT cells (40) and cDCs (33,41) reside in the PALS and marginal zones. Taken together, these findings indicate that activated pDCs are recruited from the PALS to the marginal zone where iNKT cells and cDCs reside and interact with XCR1 + DCs by forming clusters.…”