Antigen-processing machinery in human dendritic cells: up-regulation by maturation and down-regulation by tumor cells.
It has been known for some time that functional properties of dendritic cells (DC), and in particular their ability to process and present Ags to T cells, can be modulated by cytokine-induced maturation and by interactions with tumor cells. However, the molecular basis for these functional changes is unknown. We have investigated whether changes in expression of Ag-processing machinery (APM) components in DC are associated with alterations in their ability to present tumor-derived Ags to T cells. Using a panel of mAbs specific for individual APM components and a quantitative flow cytometry-based method, the level of APM components was measured in DC generated from peripheral blood monocytes of 12 normal donors and of 8 patients with cancer. Immature DC had significantly lower (p < 0.01) expression of MB1, LMP-7, LMP-10, TAP-1, and tapasin than mature DC. However, maturation in the presence of a cytokine mixture up-regulated expression of these components in DC obtained from normal donors and patients with cancer. Immature DC incubated with tumor cells had significantly lower (p < 0.001) expression of MB1, LMP-2, LMP-7, LMP-10, and endoplasmic reticulum p75 than controls. These changes were associated with a decreased ability of DC to present tumor-derived Ags to T cells, as measured in ELISPOT assays and with apoptosis of T cells in DC-T cell cultures. Thus, tumor cells have a significant suppressive effect on DC; however, ex vivo maturation of DC derived from patients with cancer in a polarizing cytokine mix restores normal expression of APM components and Ag-processing capabilities.
Whiteside
Theresa L
TL
University of Pittsburgh Cancer Institute and Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213-1863, USA. whitesidetl@msx.upmc.edu
Stanson
Joanna
J
Shurin
Michael R
MR
Ferrone
Soldano
S
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000911:Antibodies, Monoclonal / Q000276:immunology; D017951:Antigen Presentation / Q000276:immunology*; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D017920:Antiporters / Q000096:biosynthesis / Q000235:genetics; D051925:CD79 Antigens; D002454:Cell Differentiation; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D006258:Head and Neck Neoplasms / Q000097:blood / Q000473:pathology; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis / Q000235:genetics; D007535:Isomerases / Q000096:biosynthesis / Q000235:genetics; D016399:Lymphoma, T-Cell / Q000097:blood / Q000473:pathology; D008545:Melanoma / Q000097:blood / Q000473:pathology; D026901:Membrane Transport Proteins; D009000:Monocytes / Q000187:drug effects; D009097:Multienzyme Complexes / Q000096:biosynthesis / Q000235:genetics; D009369:Neoplasms / Q000276:immunology*; D046988:Proteasome Endopeptidase Complex; D019704:Protein Disulfide-Isomerases; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis / Q000235:genetics
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D017920:Antiporters; D051925:CD79 Antigens; C497881:CD79A protein, human; D016207:Cytokines; D006360:Heat-Shock Proteins; D007136:Immunoglobulins; D026901:Membrane Transport Proteins; D009097:Multienzyme Complexes; D011947:Receptors, Antigen, B-Cell; C073119:TAP1 protein, human; C107762:tapasin; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; C098948:PSMB10 protein, human; D046988:Proteasome Endopeptidase Complex; D007535:Isomerases; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human