Function of a Foxp3 cis-Element in Protecting Regulatory T Cell Identity

Function of a Foxp3 cis-Element in Protecting Regulatory T Cell Identity

• Xudong Li¹, 
• Yuqiong Liang¹, 
• Mathias LeBlanc¹, 
• Chris Benner², 
• Ye Zheng^1, , 

DOI: 10.1016/j.cell.2014.07.030

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Refers To

• Yongqiang Feng, Aaron Arvey, Takatoshi Chinen, Joris van der Veeken, Georg Gasteiger, Alexander Y. Rudensky

• Control of the Inheritance of Regulatory T Cell Identity by a cisElement in the Foxp3 Locus

• Cell, Volume 158, Issue 4, 14 August 2014, Pages 749-763
• •  PDF (3891 K)
   
  •  Supplementary content

Referred to by

• Yongqiang Feng, Aaron Arvey, Takatoshi Chinen, Joris van der Veeken, Georg Gasteiger, Alexander Y. Rudensky

• Control of the Inheritance of Regulatory T Cell Identity by a cisElement in the Foxp3 Locus

• Cell, Volume 158, Issue 4, 14 August 2014, Pages 749-763
• •  PDF (3891 K)
   
  •  Supplementary content

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Highlights

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Treg identity is challenged by destabilizing cytokine signals

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CNS2, a Foxp3 cis-element demethylated in mature Tregs, protects their identity

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CNS2 senses TCR signals key to Treg lineage specification and functional plasticity

•

Upon TCR activation, NFAT promotes the interaction of CNS2 and Foxp3 promoter

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Summary

The homeostasis of multicellular organisms requires terminally differentiated cells to preserve their lineage specificity. However, it is unclear whether mechanisms exist to actively protect cell identity in response to environmental cues that confer functional plasticity. Regulatory T (Treg) cells, specified by the transcription factor Foxp3, are indispensable for immune system homeostasis. Here, we report that conserved noncoding sequence 2 (CNS2), a CpG-rich Foxp3 intronic cis-element specifically demethylated in mature Tregs, helps maintain immune homeostasis and limit autoimmune disease development by protecting Treg identity in response to signals that shape mature Treg functions and drive their initial differentiation. In activated Tregs, CNS2 helps protect Foxp3 expression from destabilizing cytokine conditions by sensing TCR/NFAT activation, which facilitates the interaction between CNS2 and Foxp3 promoter. Thus, epigenetically markedcis-elements can protect cell identity by sensing key environmental cues central to both cell identity formation and functional plasticity without interfering with initial cell differentiation.