IKKα is required for the homeostasis of regulatory T cells and for the expansion of both regulatory and effector CD4 T cells

ABSTRACT It was reported that TNF receptor type II signaling, which has the capacity to stimulate CD4+ fork‐head box P3+ (Foxp3+) regulatory T cells (Tregs), activated the noncanonical NF‐κB pathway in an IKKα‐dependent manner. Therefore, we studied the role of IKKα in the homeostasis of Treg population. To this end, we generated a mouse strain with conditional knockout of IKKα in CD4 cells (Ikkaαf/f:CD4.Cre) that showed a >60% reduction in the number of Tregs in the thymus and peripheral lymphoid tissues, whereas the number of Foxp3‐ effector T cells (Teffs) remained at a normal level. The function of Tregs deficient in IKKα was examined using Rag1‐/‐ mice cotransferred with naive CD4 cells (nCD4s). Although wild‐type (WT) Tregs inhibited colitis induced by transfer of WT nCD4s, IKKα‐deficient Tregs failed to do so, which was associated with their inability to reconstitute Rag1‐/‐ mice. Furthermore, nCD4s deficient in IKKα also failed to reconstitute Rag1‐/‐ mice and were defective in proliferative responses in vitro and in vivo. Thus, our study reveals a novel role of IKKα in the maintenance of a normal Treg population and in the control of expansion of CD4 T cells. These properties of IKKα may be exploited as therapeutic strategies in the treatment of major human diseases.—Chen, X., Willette‐Brown, J., Wu, X., Hu, Y., Howard, O. M. Z., Hu, Y., Oppenheim, J. J. IKKα is required for the homeostasis of regulatory T cells and for the expansion of both regulatory and effector CD4 T cells. FASEB J. 29, 443‐454 (2015). www.fasebj.org