title: Tapasin shapes immunodominance hierarchies according to the kinetic stability of peptide-MHC class I complexes.
abstract: 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.
authors.affiliation: Cancer Sciences Division, University of Southampton School of Medicine, SGH, Southampton, UK. S.M.Thirdborough@soton.ac.uk
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Thirdborough
authors.forename: Joanne S
authors.initials: JS
authors.lastname: Roddick
authors.forename: Joanna N
authors.initials: JN
authors.lastname: Radcliffe
authors.forename: Mark
authors.initials: M
authors.lastname: Howarth
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
authors.forename: Tim
authors.initials: T
authors.lastname: Elliott
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D045142:Cross-Priming / Q000276:immunology; D004527:Egg Proteins / Q000276:immunology / Q000493:pharmacokinetics*; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000493:pharmacokinetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology / Q000493:pharmacokinetics*; D010446:Peptide Fragments; D015398:Signal Transduction / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics
chemical_list: D004527:Egg Proteins; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D026901:Membrane Transport Proteins; C110366:OVA-8; D010446:Peptide Fragments; D019444:Vaccines, DNA; C107762:tapasin; D010047:Ovalbumin