Epigenetic remodeling of the IL-2 and IFN-γ loci in memory CD8 T cells is influenced by CD4 T cells

JK Northrop, RM Thomas, AD Wells… - The Journal of …, 2006 - journals.aai.org
JK Northrop, RM Thomas, AD Wells, H Shen
The Journal of Immunology, 2006journals.aai.org
Abstract 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 …
Abstract
Memory T cells (T M) 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 T M undergo homeostatic proliferation over time. We examined the molecular basis underlying this enhanced functional capacity in CD8 T M by comparing them to defective CD8 T M generated in the absence of CD4 T cells. Unhelped CD8 T M are defective in many functions, including the immediate expression of cytokines, such as IL-2 and IFN-γ. Our data show that this defect in IL-2 and IFN-γ 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-γ loci and substantial histone acetylation at the IFN-γ 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-γ locus. Thus, CD4 T cell help influences epigenetic modification during CD8 T M differentiation and these epigenetic changes provide a molecular basis for the enhanced responsiveness and the maintenance of a “ready-to-respond” state in CD8 T M.
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