T cell receptor signaling induces expression of lysine demethylase KDM6B to maintain Treg homeostasis
Minghong He, Beisi Xu, Pria G. Bose, Morgan J. McCullough, Rani S. Sellers, Xinying Zong, Wenjie Qi, Brianna L. Banten, Miriya K. Tune, Matthew P. Zimmerman, Genevieve Mullins, Brian C. Miller, J. Justin Milner, Jason K. Whitmire, Ageliki Tsagaratou, Karl B. Shpargel, Claire M. Doerschuk, Yong-Dong Wang, Jacob A. Steele, Shondra M. Pruett-Miller, Yongqiang Feng, Jason R. Mock
Minghong He, Beisi Xu, Pria G. Bose, Morgan J. McCullough, Rani S. Sellers, Xinying Zong, Wenjie Qi, Brianna L. Banten, Miriya K. Tune, Matthew P. Zimmerman, Genevieve Mullins, Brian C. Miller, J. Justin Milner, Jason K. Whitmire, Ageliki Tsagaratou, Karl B. Shpargel, Claire M. Doerschuk, Yong-Dong Wang, Jacob A. Steele, Shondra M. Pruett-Miller, Yongqiang Feng, Jason R. Mock
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Research Article Immunology Pulmonology

T cell receptor signaling induces expression of lysine demethylase KDM6B to maintain Treg homeostasis

Abstract

Tregs expressing forkhead box P3 (FOXP3) play crucial roles in maintaining immune tolerance and tissue integrity. EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, is known as a key regulator of Treg identity and suppressive function upon activation. Here, we demonstrate that the H3K27 lysine demethylase KDM6B, which catalyzes the opposing reaction to EZH2, is also required for Treg identity and function after activation. Treg-specific deletion of Kdm6b impaired tissue Treg fate and function. KDM6B was upregulated after T cell antigen receptor signaling in Tregs and contributed to the regulation of Treg-associated gene expression through both direct and indirect mechanisms. A subset of Treg functional genes were direct targets of KDM6B and were co-occupied by FOXP3 at cis-regulatory regions, where KDM6B recruitment limited H3K27me3 accumulation. More broadly, KDM6B-dependent H3K27 demethylation facilitated Treg gene expression programs that supported tissue Treg homeostasis.

Authors

Minghong He, Beisi Xu, Pria G. Bose, Morgan J. McCullough, Rani S. Sellers, Xinying Zong, Wenjie Qi, Brianna L. Banten, Miriya K. Tune, Matthew P. Zimmerman, Genevieve Mullins, Brian C. Miller, J. Justin Milner, Jason K. Whitmire, Ageliki Tsagaratou, Karl B. Shpargel, Claire M. Doerschuk, Yong-Dong Wang, Jacob A. Steele, Shondra M. Pruett-Miller, Yongqiang Feng, Jason R. Mock

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Figure 5

KDM6B regulates chromatin accessibility and transcriptional programs in Tregs after TCR stimulation.

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KDM6B regulates chromatin accessibility and transcriptional programs in ...
(A) Comparison of ATAC-Seq signal (FPKM) at genomic regions with differential accessibility in TCR- versus mock-treated WT Tregs (P < 0.05; log2FC > 0.5). *P < 0.05 and ****P < 0.0001, by unpaired 2-tailed t test. Three replicates were combined for analysis. (B and C) Transcription factor binding motif enrichment analysis of ATAC-Seq peaks under the indicated conditions. (D–G) Integration of ATAC-Seq and RNA-Seq datasets showing overlap between differentially accessible chromatin regions and DEGs under the indicated conditions. Three replicates were combined for analysis. (H) ATAC-Seq modification tracks for Il1rl1 (2 alternative transcripts shown) comparing Foxp3YFP-Cre or Kdm6bΔTreg splenic Tregs in the presence or absence of TCR stimulation. Data were pooled from 3 replicates for presentation. (I) Overlap between ATAC-Seq peaks (*P < 0.05) and KDM6B ChIP-Seq binding sites. **P < 0.01 by 2-tailed t test. Three replicates were combined for analysis.