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

Abstract

Forkhead 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) IκB(NS) drives Foxp3 expression via association with the promoter and the conserved noncoding sequence 3 (CNS3) of the Foxp3 locus. Consequently, IκB(NS) 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 IκB(NS)-deficient CD25(-)CD4(+) T cells adoptively transferred into immunodeficient recipients. Importantly, IκB(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 Carma1, IκB(NS)-deficient mice do not show reduced Treg precursor cells. Our results demonstrate that IκB(NS) critically regulates Treg cell development in the thymus and during gut inflammation, indicating that strategies targeting IκB(NS) could modulate the Treg cell compartment.

IκBNS Regulates Murine Th17 Differentiation during Gut Inflammation and Infection

“…We recently reported that IkB NS regulates the induction of Foxp3 expression in Tregs (17 (17), whereas in differentiated CD4 + Th cells, it regulates proliferation and effector cytokine production. Thus, our findings In addition to the autoimmune models of colitis, we addressed the question of whether IkB NS is instrumental for Th17 responses during infection.…”

“…Body weight was measured during the progression of colitis. Consistency of the stool and rectal bleeding were scored as described previously (17). At the end of the experiment, the length of the colon was measured from the cecum to the anus.…”

“…To analyze histological changes in the colon, colon samples were fixed in 4% paraformaldehyde, embedded in paraffin, and cut into 2-mm sections. The colon sections were deparaffinized and stained with H&E. Fixed colon samples were scored in a blinded manner, as described earlier (17). The histological score of DSS colitis is the sum of the individual scores for inflammatory cell infiltrations and tissue damage.…”

“…Body weight was monitored during colitis progression. Consistency of the stool and rectal bleeding were scored as described earlier (17). The length of the colon was measured from the cecum to the anus, and colon samples were scored in a blinded manner, as described previously (17).…”

“…We reported recently that the atypical NF-kB inhibitor IkB NS regulates regulatory T cell (Treg) generation (17 …”