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Blood, 15 December 2003, Vol. 102, No. 13, pp. 4448-4455.
Prepublished online as a Blood First Edition Paper on August 21, 2003; DOI 10.1182/blood-2003-06-1801.
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IMMUNOBIOLOGY
Characterization of the MHC class I cross-presentation pathway for cell-associated antigens by human dendritic cells
Jean Francois Fonteneau,
Daniel G. Kavanagh,
Margareta Lirvall,
Catherine Sanders,
Timothy L. Cover,
Nina Bhardwaj, and
Marie Larsson
From the Institute de Biologie, INSERM U463 44093 Nantes, France; School of Medicine, New York University, New York, NY; Department of Cell Biology, University of Linköping, Linköping, Sweden; Graduate School of Art and Science, Emory University, Atlanta, GA; Department of Medicine and Microbiology and Immunology, Vanderbilt University School of Medicine and VA Medical Center, Nashville, TN.
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. (Blood. 2003;102:4448-4455)
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