lunes, 18 de agosto de 2014

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

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

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

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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


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.

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