期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：1
页码：202-207
DOI：10.1073/pnas.1418690112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceWe have shown previously that dipeptides can support efficient in vitro folding of the MHC class I molecules. Here, we describe the discovery of dipeptides that catalyze the dissociation of low- and high-affinity peptides from class I and their replacement for exogenous peptides of interest, on both recombinant and cell surface HLA-A*02:01, HLA-B*27:05, and H-2Kb molecules. Understanding peptide exchange on class I will help us understand peptide optimization in live cells. We demonstrate that the peptide-exchange technology can be used to produce epitope-specific MHC tetramers much faster and more easily than possible with techniques currently available and to enhance peptide loading onto live cells for cancer immunotherapy. Further applications include allotype specific peptide epitope elution from tumor cells. Peptide ligand selection by MHC class I molecules, which occurs by iterative optimization, is the centerpiece of immunodominance in antiviral and antitumor immune responses. For its understanding, the molecular mechanisms of peptide binding and dissociation by class I molecules must be elucidated. To this end, we have investigated dipeptides that bind to the F pocket of class I molecules. We find that they accelerate the dissociation of prebound peptides of both low and high affinity, suggesting a mechanism of action for the peptide-exchange chaperone tapasin. Peptide exchange on class I molecules also has practical uses in epitope discovery and T-cell monitoring.
