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.

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Identifiers

ORCID for Ian Galea: orcid.org/0000-0002-1268-5102

ORCID for Tim Elliott: orcid.org/0000-0003-1097-0222

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