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Loci in Memory CD8 T Cells Is Influenced by CD4 T Cells1
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* Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
Joseph Stokes, Jr. Research Institute, Children’s Hospital of Philadelphia, Philadelphia, PA 19104; and
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
Memory T cells (TM) are able to rapidly exert effector functions, including immediate effector cytokine production upon re-encounter with Ag, which is critical for protective immunity. Furthermore, this poised state is maintained as TM undergo homeostatic proliferation over time. We examined the molecular basis underlying this enhanced functional capacity in CD8 TM by comparing them to defective CD8 TM generated in the absence of CD4 T cells. Unhelped CD8 TM are defective in many functions, including the immediate expression of cytokines, such as IL-2 and IFN-
. Our data show that this defect in IL-2 and IFN- production is independent of clonal selection, functional avidity maturation, and the integrity of proximal TCR signaling, but rather involves epigenetic modification of these cytokine genes. Activated Ag-specific CD8 T cells exhibit rapid DNA demethylation at the IL-2 and IFN- loci and substantial histone acetylation at the IFN- promoter and enhancer regions. These epigenetic modifications occur early after infection at the effector stage and are maintained through memory development. However, activated unhelped CD8 T cells, which fail to develop into functional memory and are incapable of rapid cytokine production, exhibit increased DNA methylation at the IL-2 promoter and fail to acetylate histones at the IFN- locus. Thus, CD4 T cell help influences epigenetic modification during CD8 TM differentiation and these epigenetic changes provide a molecular basis for the enhanced responsiveness and the maintenance of a "ready-to-respond" state in CD8 TM.
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