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P-Glycoprotein Plays an Insignificant Role in the Presentation of Antigenic Peptides to CD8⁺ T Cells

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892-0440 [G. R., J. R. B., J. W. Y.]; and Laboratories of Molecular Biology [M. R., M. M. G.] and Cell Biology [C. A. H., I. P.], Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892

Most antigenic peptides presented to CD8⁺ T cells are generated from cytosolic precursors and are translocated by TAP into the endoplasmic reticulum, where they associate with MHC class I molecules. TAP-deficient cells exhibit a limited capacity to deliver peptides from cytosolic proteins to class I molecules. One candidate for an alternative peptide transporter is P-glycoprotein, which transports numerous substances, including peptides, across membranes. Elevation of P-glycoprotein expression is partially responsible for the resistance developed by neoplasias to chemotherapeutic drugs. Overexpression of P-glycoprotein has been reported to enhance the expression of class I molecules. Here, we investigated the role of P-glycoprotein in the generation of peptide-MHC complexes. We were unable to detect P-glycoprotein-mediated transport of synthetic peptides into the endoplasmic reticulum of either T2 cells (TAP-deficient) infected with a recombinant vaccinia virus (rVV) expressing P-glycoprotein or drug-resistant cells in which TAP is inactivated by a peptide from the herpes simplex virus ICP47 protein. Expression of rVV-encoded P-glycoprotein in T2 cells was unable to enhance cell surface expression of any of three MHC class I allomorphs tested. rVV-mediated expression of P-glycoprotein enabled T2 cells to produce limited amounts of class I-peptide complexes from cytosolic antigens, but this was not blocked by a drug that inhibits its transporter function, and a similar degree of presentation was mediated by functionally inactive mutated forms of P-glycoprotein. Thus, this was a nonspecific effect that we attributed to diminished membrane integrity resulting from P-glycoprotein overexpression. Taken together, our findings cast serious doubts that P-glycoprotein is a biologically significant transporter of cytosolic peptides.

¹ Present address: Institute of Virology, Slovak Academy of Sciences, 84246 Bratislava, Slovakia.

² To whom requests for reprints should be addressed, at Room 213, Building 4, NIH, Bethesda, MD 20892-0440. Phone: (301) 496-7533; Fax: (301) 402-7362; E-mail: jyewdell@nih.gov

Received 5/20/98. Accepted 8/18/98.

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