Limited Phenotypic and Functional Plasticity of Influenza Virus-Specific Memory CD8(+) T Cells during Activation in an Alternative Cytokine Environment

摘要

Naive CD8(+) T cells show phenotypic, functional, and epigenetic plasticity, enabling differentiation into distinct cellular states. However, whether memory CD8(+) T cells demonstrate similar flexibility upon recall is poorly understood. We investigated the potential of influenza A virus (IAV)-specific memory CD8(+) T cells from mice to alter their phenotype and function in response to reactivation in the presence of IL-4 and anti-IFN-gamma Ab (type 2 conditions). Compared with naive CD8(+) T cells, only a small proportion of IAV-specific memory T cells exhibited phenotypic and functional plasticity after clonal activation under type 2 conditions. The potential for modulation of cell-surface phenotype (CD8 alpha expression) was associated with specific epigenetic changes at the Cd8 alpha locus, was greater in central memory T cells than effector memory T cells, and was observed in endogenous memory cells of two TCR specificities. Using a novel technique for intracellular cytokine staining of small clonal populations, we showed that IAV-specific memory CD8(+) T cells reactivated under type 2 conditions displayed robust IFN-gamma expression and, unlike naive CD8(+) T cells activated under type 2 conditions, produced little IL-4 protein. Secondary activation of memory cells under type 2 conditions increased GATA-3 levels with minimal change in T-bet levels. These data suggest that a small population of memory cells, especially central memory T cells, exhibits plasticity; however, most IAV-specific memory CD8(+) T cells resist reprogramming upon reactivation and retain the functional state established during priming.