Abstract
Abstract Regulatory T (Treg) cells bearing a diverse antigen receptor repertoire suppress pathogenic T cells and maintain immune homeostasis during their long lifespan. How robust Treg function is determined genetically remains elusive. Here, we investigate the regulatory space of the cis-regulatory elements of Treg lineage–specifying factor Foxp3 known as distinct modules promoting Treg cell induction or lineage stability. Their single deficiencies cause mild, if any, immune dysregulation, leaving the key transcriptional mechanisms of the Foxp3 gene determining Treg suppressive capacity uncertain. Therefore, we examined the collective activities of Foxp3 enhancers and found that they coordinate to maximize Treg cell induction and stability through distinct modes. Thus, the induction and maintenance of a diverse, stable Treg cell repertoire rely on combinatorial Foxp3 enhancers acting in a stage-specific manner, improving our understanding of the genetic determinants of Treg suppressive capacity.
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