IκBNS Protein Mediates Regulatory T Cell Development via Induction of the Foxp3 Transcription Factor

SummaryForkhead box P3 positive (Foxp3+) regulatory T (Treg) cells suppress immune responses and regulate peripheral tolerance. Here we show that the atypical inhibitor of NFκB (IκB) IκBNS drives Foxp3 expression via association with the promoter and the conserved noncoding sequence 3 (CNS3) of the Foxp3 locus. Consequently, IκBNS deficiency leads to a substantial reduction of Foxp3+ Treg cells in vivo and impaired Foxp3 induction upon transforming growth factor-β (TGF-β) treatment in vitro. Moreover, fewer Foxp3+ Treg cells developed from IκBNS-deficient CD25−CD4+ T cells adoptively transferred into immunodeficient recipients. Importantly, IκBNS was required for the transition of immature GITR+CD25+Foxp3− thymic Treg cell precursors into Foxp3+ cells. In contrast to mice lacking c-Rel or Carma1, IκBNS-deficient mice do not show reduced Treg precursor cells. Our results demonstrate that IκBNS critically regulates Treg cell development in the thymus and during gut inflammation, indicating that strategies targeting IκBNS could modulate the Treg cell compartment