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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.

Original publication

DOI

10.1002/eji.201142010

Type

Journal article

Journal

European journal of immunology

Publication Date

01/2012

Volume

42

Pages

256 - 263

Addresses

Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.

Keywords

Antigen-Presenting Cells, CD8-Positive T-Lymphocytes, Animals, Mice, Inbred C57BL, Mice, Transgenic, Mice, Vaccines, DNA, Histocompatibility Antigens Class I, Epitopes, T-Lymphocyte, Immunodominant Epitopes, Immunization, Lymphocyte Activation, Kinetics, Half-Life