Forced expression of HLA-DM at the surface of dendritic cells increases loading of synthetic peptides on MHC class II molecules and modulates T cell responses

Abstract

Adoptive transfer of autologous dendritic cells (DCs) loaded with tumor-associated CD4 and CD8 T cell epitopes represents a promising avenue for the immunotherapy of cancer. In an effort to increase the loading of therapeutic synthetic peptides on MHC II molecules, we used a mutant of HLA-DM (DMY) devoid of its lysosomal sorting motif and that accumulates at the cell surface. Transfection of DMY into HLA-DR(+) cells resulted in increased loading of the exogenously supplied HA(307-318) peptide, as well as increased stimulation of HA-specific T cells. Also, on transduction in mouse and human DCs, DMY increased loading of HEL(48-61) and of the tumor Ag-derived gp100(174-190) peptides, respectively. Interestingly, expression of DMY at the surface of APCs favored Th1 differentiation over Th2. Finally, we found that DMY(-) and DMY(+) mouse APCs differentially stimulated T cell hybridomas sensitive to the fine conformation of peptide-MHC II complexes. Taken together, our results suggest that the overexpression of HLA-DMY at the plasma membrane of DCs may improve quantitatively, but also qualitatively, the presentation of CD4 T cell epitopes in cellular vaccine therapies for cancer.