CD4 expression in effector T cells depends on DNA demethylation over a developmentally established stimulus-responsive element

Athmane Teghanemt, Priyanjali Pulipati, Kara Misel-Wuchter, Kenneth Day, Matthew S. Yorek, Ren Yi, Henry L. Keen, Christy Au, Thorsten Maretzky, Prajwal Gurung, Dan R. Littman and Priya D. Issuree ()
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Athmane Teghanemt: Carver College of Medicine University of Iowa
Priyanjali Pulipati: Carver College of Medicine University of Iowa
Kara Misel-Wuchter: Carver College of Medicine University of Iowa
Kenneth Day: Zymo Research Corporation
Matthew S. Yorek: Carver College of Medicine University of Iowa
Ren Yi: New York University
Henry L. Keen: University of Iowa
Christy Au: New York University School of Medicine
Thorsten Maretzky: Carver College of Medicine University of Iowa
Prajwal Gurung: Carver College of Medicine University of Iowa
Dan R. Littman: New York University School of Medicine
Priya D. Issuree: Carver College of Medicine University of Iowa

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract The epigenetic patterns that are established during early thymic development might determine mature T cell physiology and function, but the molecular basis and topography of the genetic elements involved are not fully known. Here we show, using the Cd4 locus as a paradigm for early developmental programming, that DNA demethylation during thymic development licenses a novel stimulus-responsive element that is critical for the maintenance of Cd4 gene expression in effector T cells. We document the importance of maintaining high CD4 expression during parasitic infection and show that by driving transcription, this stimulus-responsive element allows for the maintenance of histone H3K4me3 levels during T cell replication, which is critical for preventing de novo DNA methylation at the Cd4 promoter. A failure to undergo epigenetic programming during development leads to gene silencing during effector T cell replication. Our study thus provides evidence of early developmental events shaping the functional fitness of mature effector T cells.

Date: 2022
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DOI: 10.1038/s41467-022-28914-4

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