Epitope Density Influences CD8+ Memory T Cell Differentiation

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Abstract
The generation of long-lived memory T cells is critical for successful vaccination but the factors controlling their differentiation are still poorly defined. We tested the hypothesis that the strength of T cell receptor (TCR) signaling contributed to memory CD8+ T cell generation. We manipulated the density of antigenic epitope presented by dendritic cells to mouse naïve CD8+ T cells, without varying TCR affinity. Our results show that a two-fold decrease in antigen dose selectively affects memory CD8+ T cell generation without influencing T cell expansion and acquisition of effector functions. Moreover, we show that low antigen dose alters the duration of the interaction between T cells and dendritic cells and finely tunes the expression level of the transcription factors Eomes and Bcl6. Furthermore, we demonstrate that priming with higher epitope density results in a 2-fold decrease in the expression of Neuron-derived orphan nuclear receptor 1 (Nor-1) and this correlates with a lower level of conversion of Bcl-2 into a pro-apoptotic molecule and an increased number of memory T cells. Our results show that the amount of antigen encountered by naïve CD8+ T cells following immunization with dendritic cells does not influence the generation of functional effector CD8+ T cells but rather the number of CD8+ memory T cells that persist in the host. Our data support a model where antigenic epitope density sensed by CD8+ T cells at priming influences memory generation by modulating Bcl6, Eomes and Nor-1 expression.

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