High Epitope Expression Levels Increase Competition between T Cells

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Abstract
Both theoretical predictions and experimental findings suggest that T cell populations can compete with each other. There is some debate on whether T cells compete for aspecific stimuli, such as access to the surface on antigen-presenting cells (APCs) or for specific stimuli, such as their cognate epitope ligand. We have developed an individual-based computer simulation model to study T cell competition. Our model shows that the expression level of foreign epitopes per APC determines whether T cell competition is mainly for specific or aspecific stimuli. Under low epitope expression, competition is mainly for the specific epitope stimuli, and, hence, different epitope-specific T cell populations coexist readily. However, if epitope expression levels are high, aspecific competition becomes more important. Such between-specificity competition can lead to competitive exclusion between different epitope-specific T cell populations. Our model allows us to delineate the circumstances that facilitate coexistence of T cells of different epitope specificity. Understanding mechanisms of T cell coexistence has important practical implications for immune therapies that require a broad immune response. Pathogens are masters of disguise, and frequently escape recognition by the immune response. Therefore, broad immune responses, directed at many epitopes of the pathogen, are thought to improve control of infection. There is evidence that competition between immune cells of different epitope specificity reduces the breadth of the immune response. It has been suggested that the resource that T cells compete for is access to antigen-presenting cells (APCs). However, the experimental data regarding competition for access to APCs is controversial. In this study, Scherer, Salathé, and Bonhoeffer have used an individual-based model to investigate the mechanisms of T cell competition. They find that T cells only compete for access to APCs when epitopes are expressed abundantly on APCs. In contrast, when epitope expression is limiting, competition is for the specific epitope rather than for access to APCs. The distinction between competition for epitope and for access to APCs is relevant because the model predicts qualitatively different outcomes for either case. When competition is for the specific epitope, different epitope-specific T cell responses coexist readily and hence the immune response is broad. However, when T cells compete for access to APCs, immunodominant T cell responses can outcompete subdominant ones, which leads to narrow immune responses.