Utilizing TAPBPR to promote exogenous peptide loading onto cell surface MHC I molecules.

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The repertoire of peptides displayed at the cell surface by MHC I molecules is shaped by two intracellular peptide editors, tapasin and TAPBPR. While cell-free assays have proven extremely useful in identifying the function of both of these proteins, here we explored whether a more physiological system could be developed to assess TAPBPR-mediated peptide editing on MHC I. We reveal that membrane-associated TAPBPR targeted to the plasma membrane retains its ability to function as a peptide editor and efficiently catalyzes peptide exchange on surface-expressed MHC I molecules. Additionally, we show that soluble TAPBPR, consisting of the luminal domain alone, added to intact cells, also functions as an effective peptide editor on surface MHC I molecules. Thus, we have established two systems in which TAPBPR-mediated peptide exchange on MHC class I can be interrogated. Furthermore, we could use both plasma membrane-targeted and exogenous soluble TAPBPR to display immunogenic peptides on surface MHC I molecules and consequently induce T cell receptor engagement, IFN-γ secretion, and T cell-mediated killing of target cells. Thus, we have developed an efficient way to by-pass the natural antigen presentation pathway of cells and load immunogenic peptides of choice onto cells. Our findings highlight a potential therapeutic use for TAPBPR in increasing the immunogenicity of tumors in the future.

HLA, MHC, TAPBPR/TAPBPL, antigen presentation, antigen processing, Animals, Antigen Presentation, HeLa Cells, Histocompatibility Antigens Class I, Humans, Immunity, Cellular, Immunoglobulins, Interferon-gamma, MCF-7 Cells, Membrane Proteins, Mice, Mice, Knockout, Peptides, Receptors, Antigen, T-Cell, T-Lymphocytes
Journal Title
Proc Natl Acad Sci U S A
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Proceedings of the National Academy of Sciences
Wellcome Trust (104647/Z/14/Z)
Cancer Research UK (C14303/A17197)
Medical Research Council (MR/K021087/1)
Medical Research Council (MR/S00081X/1)
Wellcome Trust (107609/Z/15/Z)