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Peptide loading of MHC class I molecules involves multiple cofactors including tapasin. We showed previously in vitro that tapasin edits the peptide repertoire by favoring the binding of peptides with slow dissociation rates. Here, using tapasin-deficient mice and a DNA vaccine that primes directly, we confirm that tapasin establishes hierarchical responses in vivo according to peptide-MHC stability. In contrast, this hierarchy is lost when the peptides are cross-presented via an alternative DNA vaccine. By regulating transgene expression, we found that the dominant response modifier was antigen persistence. Our findings reveal strategies for activating T cells against low-affinity peptides, of potential importance for patients with repertoires narrowed by deletional tolerance.

Original publication

DOI

10.1002/eji.200737832

Type

Journal article

Journal

European journal of immunology

Publication Date

02/2008

Volume

38

Pages

364 - 369

Addresses

Cancer Sciences Division, University of Southampton School of Medicine, SGH, Southampton, UK. S.M.Thirdborough@soton.ac.uk

Keywords

CD8-Positive T-Lymphocytes, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Peptide Fragments, Ovalbumin, Membrane Transport Proteins, Egg Proteins, Vaccines, DNA, Histocompatibility Antigens Class I, Immunodominant Epitopes, Signal Transduction, Cross-Priming