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

Forkhead box P3 positive (Foxp3(+)) regulatory T (Treg) cells suppress immune responses and regulate peripheral tolerance. Here we show that the atypical inhibitor of NF kappa B (I kappa B) I kappa B-NS drives Foxp3 expression via association with the promoter and the conserved noncoding sequence 3 (CNS3) of the Foxp3 locus. Consequently, I kappa B-NS deficiency leads to a substantial reduction of Foxp3+ Treg cells in vivo and impaired Foxp3 induction upon transforming growth factor-beta (TGF-13) treatment in vitro. Moreover, fewer Foxp3+ Treg cells developed from I kappa B-NS-deficient CD25(-)CD4(+) T cells adoptively transferred into immunodeficient recipients. Importantly, I kappa B-NS 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 Carmal, I kappa B-NS-deficient mice do not show reduced Treg precursor cells. Our results demonstrate that IkBNs critically regulates Treg cell development in the thymus and during gut inflammation, indicating that strategies targeting IkBNs could modulate the Treg cell compartment.