Epigenetic plasticity of Cd8a locus during CD8+ T-cell development and effector differentiation and reprogramming

Abstract

Modulation of CD8 coreceptor levels can profoundly affect T-cell sensitivity to antigen. Here we show that the heritable downregulation of CD8 during type 2 polarization of murine CD8+ effector T cells in vitro and in vivo is associated with CpG methylation of several regions of the Cd8a locus. These epigenetic modifications are maintained long-term in vivo following adoptive transfer. Even after extended type 2 polarization, however, some CD8low effector cells respond to interferon-γ by re-expressing CD8 and a type 1 cytokine profile in association with partial Cd8a demethylation. Cd8a methylation signatures in naive, polarized and repolarized cells are distinct from those observed during the initiation, maintenance and silencing of CD8 expression by developing T cells in the thymus. This persistent capacity for epigenetic reprogramming of coreceptor levels on effector CD8+ T cells enables the heritable tuning of antigen sensitivity in parallel with changes in type 1/type 2 cytokine balance. CD8 expression levels on peripheral CD8+ T cells are regulated during development and effector differentiation. Here, the authors show that methylation patterns at the Cd8a locus, whose product is essential for surface CD8 expression, can change during T-cell development, activation, cytokine polarization and reprogramming.