Characterization of the MHC class I cross-presentation pathway for cell-associated antigens by human dendritic cells.
Major histocompatibility complex (MHC) class I presentation of exogenous antigens is the mechanism enabling professional antigen-presenting cells (APCs) to induce CD8+ T-cell responses against viruses and tumors that do not have access to the classical MHC class I pathway. We have characterized the uptake, processing, and MHC class I cross-presentation by human dendritic cells (DCs) of cell-associated antigens derived from physiologically relevant sources, namely, vaccinia virus-infected apoptotic and necrotic cells. We show that cross-presentation is a rapid process, detectable within 2 to 4 hours after uptake of dead cells, and that proteolysis by cathepsin D in an acidic endosomal compartment is essential for cross-presentation. The presentation is abolished when the phagocytic or macropinocytic functions of the cells are inhibited and is dependent on transporter associated with antigen processing, sensitive to brefeldin A, and requires functional proteasomes. Altogether, these data suggest that antigens derived from apoptotic and necrotic cells require access to the cytosol to intersect with the conventional MHC class I pathway for presentation of cytosolic proteins.
Fonteneau
Jean Francois
JF
School of Medicine, New York University, New York, NY 10016, USA.
Kavanagh
Daniel G
DG
Lirvall
Margareta
M
Sanders
Catherine
C
Cover
Timothy L
TL
Bhardwaj
Nina
N
Larsson
Marie
M
D018528:ATP-Binding Cassette Transporters; D017951:Antigen Presentation; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002402:Cathepsin D / Q000502:physiology; D002478:Cells, Cultured / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D011992:Endosomes / Q000737:chemistry / Q000502:physiology; D015789:HLA-A2 Antigen / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000473:pathology / Q000821:virology; D009097:Multienzyme Complexes / Q000502:physiology; D009336:Necrosis; D010587:Phagocytosis; D010873:Pinocytosis; D046988:Proteasome Endopeptidase Complex; D014616:Vaccinia virus / Q000502:physiology
D018528:ATP-Binding Cassette Transporters; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; C477327:transporter associated with antigen processing (TAP); D003546:Cysteine Endopeptidases; D002402:Cathepsin D; D046988:Proteasome Endopeptidase Complex