CD8+ T‐cell cross‐competition is governed by peptide–MHC class I stability

• Published in: European journal of immunology Vol. 42; no. 1; pp. 256 - 263
• Main Authors: Galea, Ian, Stasakova, Jana, Dunscombe, Melanie S., Ottensmeier, Christian H., Elliott, Tim, Thirdborough, Stephen M.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY‐VCH Verlag 01.01.2012; Wiley Subscription Services, Inc; WILEY-VCH Verlag
• Subjects: Animals; Antigen-Presenting Cells - cytology; Antigen-Presenting Cells - immunology; Antigens; CD8+ T cells; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell division; Competition; Epitopes, T-Lymphocyte - immunology; Half-Life; Histocompatibility Antigens Class I - immunology; Immunization; Immunodominance; Immunodominant Epitopes - immunology; Kinetics; Ligands; Lymphocyte Activation - immunology; Lymphocytes; MHC; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Immunology; Peptide; T cell receptors; Vaccines, DNA - immunology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201142010

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.