Cell Reports (Sep 2016)

Acetylation of the Cd8 Locus by KAT6A Determines Memory T Cell Diversity

  • Dane M. Newman,
  • Shinya Sakaguchi,
  • Aaron Lun,
  • Simon Preston,
  • Marc Pellegrini,
  • Kseniya Khamina,
  • Andreas Bergthaler,
  • Stephen L. Nutt,
  • Gordon K. Smyth,
  • Anne K. Voss,
  • Tim Thomas,
  • Wilfried Ellmeier,
  • Gabrielle T. Belz,
  • Rhys S. Allan

DOI
https://doi.org/10.1016/j.celrep.2016.08.056
Journal volume & issue
Vol. 16, no. 12
pp. 3311 – 3321

Abstract

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How functionally diverse populations of pathogen-specific killer T cells are generated during an immune response remains unclear. Here, we propose that fine-tuning of CD8αβ co-receptor levels via histone acetylation plays a role in lineage fate. We show that lysine acetyltransferase 6A (KAT6A) is responsible for maintaining permissive Cd8 gene transcription and enabling robust effector responses during infection. KAT6A-deficient CD8+ T cells downregulated surface CD8 co-receptor expression during clonal expansion, a finding linked to reduced Cd8α transcripts and histone-H3 lysine 9 acetylation of the Cd8 locus. Loss of CD8 expression in KAT6A-deficient T cells correlated with reduced TCR signaling intensity and accelerated contraction of the effector-like memory compartment, whereas the long-lived memory compartment appeared unaffected, a result phenocopied by the removal of the Cd8 E8I enhancer element. These findings suggest a direct role of CD8αβ co-receptor expression and histone acetylation in shaping functional diversity within the cytotoxic T cell pool.

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