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BACKGROUND:Glycoproteins encoded by the major histocompatibility complex class I region (MHC class I) present peptide antigens to cytotoxic T cells (CTLs). Peptides are delivered to the site of MHC class I assembly by the transporter associated with antigen processing (TAP), and cell lines that lack this transporter are unable to present endogenous antigens to CTLs. Although it has been shown that a fraction of newly synthesized class I molecules are in physical association with TAP, it is not known whether this interaction is functionally relevant, or where on the class I molecule the TAP binding site might be. RESULTS:C1R cells transfected with a mutant HLA-A2.1 heavy chain (HC), where threonine at position 134 in the alpha 2 domain is changed to lysine (T134K), are unable to present endogenous antigens to CTLs. We have studied the biochemistry of this mutant in C1R cells, and found that a large pool of unstable empty class I HC-beta 2m (beta-2 microglobulin) heterodimers exist that are rapidly transported to the cell surface. The T134K mutant seemed to bind peptide antigens and assemble with beta 2m as efficiently as wild-type HLA-A2.1. However, we show here that the inefficiency with which T134K presents intracellular antigen is associated with its inability to interact with the TAP heterodimer. CONCLUSIONS:These experiments establish that the class I-TAP interaction is obligatory for the presentation of peptide epitopes delivered to the endoplasmic reticulum (ER) by TAP. Wild-type HLA-A2.1 molecules in TAP-deficient cells are retained in the ER, whereas T134K is rapidly released to the cell surface, but is unstable, suggesting a role for the TAP complex as an intracellular checkpoint that only affects the release of class I molecules with stably bound peptide ligands.

Original publication

DOI

10.1016/s0960-9822(02)00611-5

Type

Journal article

Journal

Current biology : CB

Publication Date

07/1996

Volume

6

Pages

873 - 883

Addresses

Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, UK.

Keywords

Cell Line, Cell Membrane, Animals, Rabbits, Humans, ATP-Binding Cassette Transporters, Histocompatibility Antigens Class I, HLA-A2 Antigen, Major Histocompatibility Complex, Binding Sites, Biological Transport, Phenotype, Point Mutation, ATP Binding Cassette Transporter, Subfamily B, Member 2, ATP Binding Cassette Transporter, Subfamily B, Member 3