TY - JOUR
T1 - 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
AU - Pezeshki, Abdul Mohammad
AU - Côté, Marie Hélène
AU - Azar, Georges A.
AU - Routy, Jean Pierre
AU - Boulassel, Mohamed Rachid
AU - Thibodeau, Jacques
PY - 2011/7/1
Y1 - 2011/7/1
N2 - 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 HA307-318 peptide, as well as increased stimulation of HA-specific T cells. Also, on transduction in mouse and human DCs, DMY increased loading of HEL48-61 and of the tumor Ag-derived gp100174-190 peptides, respectively. Interestingly, expression of DMY at the surface of APCs favored Th1 differentiation over Th2. Finally, we found that DMY2 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.
AB - 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 HA307-318 peptide, as well as increased stimulation of HA-specific T cells. Also, on transduction in mouse and human DCs, DMY increased loading of HEL48-61 and of the tumor Ag-derived gp100174-190 peptides, respectively. Interestingly, expression of DMY at the surface of APCs favored Th1 differentiation over Th2. Finally, we found that DMY2 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.
UR - http://www.scopus.com/inward/record.url?scp=79960431418&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960431418&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1002747
DO - 10.4049/jimmunol.1002747
M3 - Article
C2 - 21622867
AN - SCOPUS:79960431418
SN - 0022-1767
VL - 187
SP - 74
EP - 81
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -