title: Peptide transporter TAP mediates between competing antigen sources generating distinct surface MHC class I peptide repertoires.
abstract: We recently described a category of TAP-independent peptide-epitopes that are selectively presented by cells with processing defects in the classical MHC class I (MHC-I) pathway. Here, we studied the ER-resident ceramide synthase Trh4 as a prototypic example of these neo-antigens and found that moderate inhibition of TAP permits cell surface presentation of the Trh4 peptide. The absence of this peptide from WT cells was not related to the binding or stability of the Trh4/D(b)  complexes, or to the availability of MHC-I heavy chains, but rather to the limited expression of the antigen. Strongly elevated antigen levels were needed to reach comparable peptide display on WT as on TAP-deficient cells. Our data suggest that the normal influx of TAP-transported peptides in the ER during routine processing creates an efficient barrier for peptides from alternative processing routes. Impairment of TAP function, as commonly found in cancers and virus-infected cells, lowers this resistance allowing for MHC-I presentation of other peptide sources.
authors: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Cláudia C
authors: CC
authors: Oliveira
authors: Bianca
authors: B
authors: Querido
authors: Marjolein
authors: M
authors: Sluijter
authors: Jens
authors: J
authors: Derbinski
authors: Sjoerd H
authors: SH
authors: van der Burg
authors: Thorbald
authors: T
authors: van Hall
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; C479747:Trh4 protein, mouse; C477327:transporter associated with antigen processing (TAP)