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

摘要

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-kappa B pathway in an IKK alpha-dependent manner. Therefore, we studied the role of IKK alpha in the homeostasis of Treg population. To this end, we generated a mouse strain with conditional knockout of IKK alpha in CD4 cells (Ikk alpha(f/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 IKK alpha was examined using Rag1(-/-) mice cotransferred with naive CD4 cells (nCD4s). Although wild-type (WT) Tregs inhibited colitis induced by transfer of WT nCD4s, IKK alpha-deficient Tregs failed to do so, which was associated with their inability to reconstitute Rag1(-/-) mice. Furthermore, nCD4s deficient in IKK alpha 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 IKK alpha in the maintenance of a normal Treg population and in the control of expansion of CD4 T cells. These properties of IKK alpha may be exploited as therapeutic strategies in the treatment of major human diseases.