title: CD8+ T-cell cross-competition is governed by peptide-MHC class I stability.
abstract: A major contributing factor to the final magnitude and breadth of CD8(+)  T-cell responses to complex antigens is immunodomination, where CD8(+)  T cells recognizing their cognate ligand inhibit the proliferation of other CD8(+)  T cells engaged with the same APC. In this study, we examined how the half-life of cell surface peptide-MHC class I complexes influences this phenomenon. We found that primary CD8(+)  T-cell responses to DNA vaccines in mice are shaped by competition among responding CD8(+)  T cells for nonspecific stimuli early after activation and prior to cell division. The susceptibility of CD8(+)  T cells to 'domination' was a direct correlate of higher kinetic stability of the competing CD8(+)  T-cell cognate ligand. When high affinity competitive CD8(+)  T cells were deleted by self-antigen expression, competition was abrogated. These findings show, for the first time to our knowledge, the existence of regulatory mechanisms that direct the responding CD8(+)  T-cell repertoire toward epitopes with high-stability interactions with MHC class I molecules. They also provide an insight into factors that facilitate CD8(+)  T-cell coexistence, with important implications for vaccine design and delivery.
authors: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors: Ian
authors: I
authors: Galea
authors: Jana
authors: J
authors: Stasakova
authors: Melanie S
authors: MS
authors: Dunscombe
authors: Christian H
authors: CH
authors: Ottensmeier
authors: Tim
authors: T
authors: Elliott
authors: Stephen M
authors: SM
authors: Thirdborough
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007114:Immunization; D016056:Immunodominant Epitopes / Q000276:immunology; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019444:Vaccines, DNA / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D019444:Vaccines, DNA