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

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,...

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Bibliographic Details
Published in:Cell 2014-08, Vol.158 (4), p.734-748
Main Authors: Li, Xudong, Liang, Yuqiong, LeBlanc, Mathias, Benner, Chris, Zheng, Ye
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Cell Differentiation
Conserved Sequence
CpG Islands
Encephalomyelitis, Autoimmune, Experimental - immunology
Encephalomyelitis, Autoimmune, Experimental - metabolism
Forkhead Transcription Factors - metabolism
Gene Expression
Lymphoproliferative Disorders - immunology
Lymphoproliferative Disorders - metabolism
Mice
Molecular Sequence Data
Regulatory Sequences, Nucleic Acid
T-Lymphocytes, Regulatory - cytology
T-Lymphocytes, Regulatory - metabolism
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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 marked cis-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. [Display omitted] •Treg identity is challenged by destabilizing cytokine signals•CNS2, a Foxp3 cis-element demethylated in mature Tregs, protects their identity•CNS2 senses TCR signals key to Treg lineage specification and functional plasticity•Upon TCR activation, NFAT promotes the interaction of CNS2 and Foxp3 promoter A CpG-rich cis-element protects mature regulatory T cell identity by stabilizing the expression of Foxp3 through interaction with the Foxp3 promoter upon activation through the T cell receptor.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2014.07.030