Journal
IMMUNITY
Volume 54, Issue 5, Pages 931-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2021.03.020
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Funding
- NCI Cancer Center [P30 CA008748, P30 CA021765]
- NIH [R37 AI034206, R01 AI153138]
- Ludwig Center at the Memorial Sloan Kettering Cancer Center
- American Lebanese Syrian Associated Charities
- General Atlantic Fellowship
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The CNS0 enhancer ensures robust Treg cell differentiation early in postnatal life and cooperatively minimizes autoimmunity with other tolerance mechanisms.
Activation of the STAT5 transcription factor downstream of the Interleukin-2 receptor (IL-2R) induces expression of Foxp3, a critical step in the differentiation of regulatory T (Treg) cells. Due to the pleiotropic effects of IL-2R signaling, it is unclear how STAT5 acts directly on the Foxp3 locus to promote its expression. Here, we report that IL-2 - STAT5 signaling converged on an enhancer (CNS0) during Foxp3 induction. CNS0 facilitated the IL-2 dependent CD25(+)Foxp3(-) precursor to Treg cell transition in the thymus. Its deficiency resulted in impaired Treg cell generation in neonates, which was partially mitigated with age. While the thymic Treg cell paucity caused by CNS0 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS0 enhancer activity ensures robust Treg cell differentiation early in postnatal life and cooperatively with other tolerance mechanisms minimizes autoimmunity.
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