Control of the Inheritance of Regulatory T Cell Identity by a cis Element in the Foxp3 Locus

• Cytokine signaling regulates heritable Foxp3 expression
• Intronic element CNS2 sustains heritable Foxp3 expression in mature Treg
• IL-2-STAT5 acts on CNS2 to counteract proinflammatory cytokine signaling
• Critical roles of Treg fate heritability in physiological contexts

SummaryIn multicellular organisms, specialized functions are delegated to distinct cell types whose identity and functional integrity are maintained upon challenge. However, little is known about the mechanisms enabling lineage inheritance and their biological implications. Regulatory T (Treg) cells, which express the transcription factor Foxp3, suppress fatal autoimmunity throughout the lifespan of animals. Here, we show that a dedicated Foxp3 intronic element CNS2 maintains Treg cell lineage identity by acting as a sensor of the essential Treg cell growth factor IL-2 and its downstream target STAT5. CNS2 sustains Foxp3 expression during division of mature Treg cells when IL-2 is limiting and counteracts proinflammatory cytokine signaling that leads to the loss of Foxp3. CNS2-mediated stable inheritance of Foxp3 expression is critical for adequate suppression of diverse types of chronic inflammation by Treg cells and prevents their differentiation into inflammatory effector cells. The described mechanism may represent a general principle of the inheritance of differentiated cell states.

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