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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.

SUBMITTER: Galea I

PROVIDER: S-EPMC3744744 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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CD8+ T-cell cross-competition is governed by peptide-MHC class I stability.

Galea Ian I Stasakova Jana J Dunscombe Melanie S MS Ottensmeier Christian H CH Elliott Tim T Thirdborough Stephen M SM

European journal of immunology 20111128 1

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 CD ...[more]

PMID: 22002320

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Project description:Major Histocompatibility Complex (MHC) class I molecules enable cytotoxic T lymphocytes to destroy virus-infected or cancerous cells, thereby preventing disease progression. MHC class I molecules provide a snapshot of the contents of a cell by binding to protein fragments arising from intracellular protein turnover and presenting these fragments at the cell surface. Competing fragments (peptides) are selected for cell-surface presentation on the basis of their ability to form a stable complex with MHC class I, by a process known as peptide optimization. A better understanding of the optimization process is important for our understanding of immunodominance, the predominance of some T lymphocyte specificities over others, which can determine the efficacy of an immune response, the danger of immune evasion, and the success of vaccination strategies. In this paper we present a dynamical systems model of peptide optimization by MHC class I. We incorporate the chaperone molecule tapasin, which has been shown to enhance peptide optimization to different extents for different MHC class I alleles. Using a combination of published and novel experimental data to parameterize the model, we arrive at a relation of peptide filtering, which quantifies peptide optimization as a function of peptide supply and peptide unbinding rates. From this relation, we find that tapasin enhances peptide unbinding to improve peptide optimization without significantly delaying the transit of MHC to the cell surface, and differences in peptide optimization across MHC class I alleles can be explained by allele-specific differences in peptide binding. Importantly, our filtering relation may be used to dynamically predict the cell surface abundance of any number of competing peptides by MHC class I alleles, providing a quantitative basis to investigate viral infection or disease at the cellular level. We exemplify this by simulating optimization of the distribution of peptides derived from Human Immunodeficiency Virus Gag-Pol polyprotein.

Dataset Information

CD8+ T-cell cross-competition is governed by peptide-MHC class I stability.

Publications

CD8+ T-cell cross-competition is governed by peptide-MHC class I stability.

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