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
Affiliations
Dane M. Newman
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Shinya Sakaguchi
Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna 1090, Austria
Aaron Lun
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Simon Preston
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Marc Pellegrini
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Kseniya Khamina
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
Andreas Bergthaler
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
Stephen L. Nutt
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Gordon K. Smyth
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Anne K. Voss
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Tim Thomas
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Wilfried Ellmeier
Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna 1090, Austria
Gabrielle T. Belz
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Rhys S. Allan
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
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.
