title: 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 CD8(low) 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.
authors.affiliation: 1] Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Victoria 3010, Australia [2].
authors.forename: Kim L
authors.initials: KL
authors.lastname: Harland
authors.affiliation: 1] Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Victoria 3010, Australia [2].
authors.forename: E Bridie
authors.initials: EB
authors.lastname: Day
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
authors.forename: Simon H
authors.initials: SH
authors.lastname: Apte
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Victoria 3010, Australia.
authors.forename: Brendan E
authors.initials: BE
authors.lastname: Russ
authors.affiliation: 1] Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Victoria 3010, Australia [2] Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Doherty
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Victoria 3010, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Turner
authors.affiliation: 1] Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Victoria 3010, Australia [2] WHO Collaborating Centre for Reference and Research on Influenza, 10 Wreckyn Street, North Melbourne, Victoria 3051, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Kelso
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000235:genetics* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002454:Cell Differentiation; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D016207:Cytokines