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

Kim L. Harland, E. Bridie Day, Simon H. Apte, Brendan E. Russ, Peter C. Doherty, Stephen J. Turner and Anne Kelso ()
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Kim L. Harland: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
E. Bridie Day: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Simon H. Apte: QIMR Berghofer Medical Research Institute
Brendan E. Russ: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Peter C. Doherty: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Stephen J. Turner: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Anne Kelso: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4547

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