Abstract
Memory CD8 T cells confer increased protection to immune hosts upon secondary viral, bacterial, and parasitic infections. The level of protection provided depends on the numbers, quality (functional ability), and location of memory CD8 T cells present at the time of infection. While primary memory CD8 T cells can be maintained for the life of the host, the full extent of phenotypic and functional changes that occur over time after initial antigen encounter remains poorly characterized. Here we show that critical properties of circulating primary memory CD8 T cells, including location, phenotype, cytokine production, maintenance, secondary proliferation, secondary memory generation potential, and mitochondrial function change with time after infection. Interestingly, phenotypic and functional alterations in the memory population are not due solely to shifts in the ratio of effector (CD62Llo) and central memory (CD62Lhi) cells, but also occur within defined CD62Lhi memory CD8 T cell subsets. CD62Lhi memory cells retain the ability to efficiently produce cytokines with time after infection. However, while it is was not formally tested whether changes in CD62Lhi memory CD8 T cells over time occur in a cell intrinsic manner or are due to selective death and/or survival, the gene expression profiles of CD62Lhi memory CD8 T cells change, phenotypic heterogeneity decreases, and mitochondrial function and proliferative capacity in either a lymphopenic environment or in response to antigen re-encounter increase with time. Importantly, and in accordance with their enhanced proliferative and metabolic capabilities, protection provided against chronic LCMV clone-13 infection increases over time for both circulating memory CD8 T cell populations and for CD62Lhi memory cells. Taken together, the data in this study reveal that memory CD8 T cells continue to change with time after infection and suggest that the outcome of vaccination strategies designed to elicit protective memory CD8 T cells using single or prime-boost immunizations depends upon the timing between antigen encounters.
Highlights
Memory CD8 T cells provide immune hosts with enhanced protection from pathogenic infection due to an increased precursor frequency of antigen (Ag)-specific cells, widespread localization to both lymphoid and non-lymphoid tissues, and ability to rapidly execute effector functions such as cytokine production and cytolysis compared to naïve CD8 T cells [1,2,3]
Memory CD8 T cells persist at higher numbers and have enhanced functional abilities compared to naïve cells, providing immune hosts with increased protection from viral, bacterial, or parasitic infection
We show that the phenotype and functions of circulating memory CD8 T cells, including cytokine production, proliferation, and mitochondrial function following re-infection improves with time after infection
Summary
Memory CD8 T cells provide immune hosts with enhanced protection from pathogenic infection due to an increased precursor frequency of antigen (Ag)-specific cells, widespread localization to both lymphoid and non-lymphoid tissues, and ability to rapidly execute effector functions such as cytokine production and cytolysis compared to naïve CD8 T cells [1,2,3]. Expression of CD62L and CD27 (markers of central memory cells) increases, indicating that the subset composition of the memory population changes with time after infection. Functions such as cytokine production, proliferation, and memory generation following Ag re-encounter, increase with time [24,25,26,27,28]. The full extent of phenotypic and functional alterations that occur within the memory CD8 T cell population with time after infection, remains poorly characterized It is unclear if alterations are due solely to differences in subset composition of memory CD8 T cell populations, or to changes within defined memory subsets. These are important questions to address, as the level of protection provided against systemic infections may change with time following initial infection and/or vaccination
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