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 + forkhead box P3 + (Foxp3 + ) regulatory T cells (Tregs), activated the noncanonical NF-kB pathway in an IKKa-dependent manner. Therefore, we studied the role of IKKa in the homeostasis of Treg population. To this end, we generated a mouse strain with conditional knockout of IKKa in CD4 cells (Ikka 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 2 effector T cells (Teffs) remained at a normal level. The function of Tregs deficient in IKKa was examined using Rag1 2/2 mice cotransferred with naive CD4 cells (nCD4s). Although wild-type (WT) Tregs inhibited colitis induced by transfer of WT nCD4s, IKKa-deficient Tregs failed to do so, which was associated with their inability to reconstitute Rag1 2/2 mice. Furthermore, nCD4s deficient in IKKa also failed to reconstitute Rag1 2/2 mice and were defective in proliferative responses in vitro and in vivo. Thus, our study reveals a novel role of IKKa in the maintenance of a normal Treg population and in the control of expansion of CD4 T cells. These properties of IKKa 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. IKKa 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

Macrophage IKKα Deficiency Suppresses Akt Phosphorylation, Reduces Cell Survival, and Decreases Early Atherosclerosis

“…In addition, we found decreased numbers of T-cells in blood of IKKα −/− →LDLR −/− mice and these data support the view that IKKα is an essential component of T-cell regulatory function 35 . Finally, our IKKα −/− →LDLR −/− mice had significantly diminished numbers of blood B-cells and this is in harmony with the notion that IKKα is essential for B-cell maturation 10 .…”

The contribution of NF‐κB signalling to immune regulation and tolerance

“…Despite the fact that Ltbr À/À mice contain no alterations in the number of thymic Treg [52], anti-RANKL-treated [43] or anti-CD40L-treated [53] WT mice, Cd40 À/À mice [54], mice deficient for IKKa specifically in CD4 + T cells [55], aly/aly mice [6] and Nik À/À mice [6,56] all contain less Treg in the thymus. Furthermore, WT recipients of Relb À/À mTEC grafts have decreased numbers of Treg and Treg precursors compared to recipients of WT grafts [57].…”

TCR signaling to NF-κB and mTORC1: Expanding roles of the CARMA1 complex

“…On the other hand, the loss of NIK in T-cell compartment does not seem to impair the development, proliferation, or suppressive function of Treg cells (Murray, 2013). Another study suggests that IKKα not only regulates the homeostasis of Treg cells but also the expansion and effector function of Treg cells (Chen et al, 2015). T cell-specific ablation of IKKα causes more than 60% reduction in the number of Tregs in both the thymus and the peripheral lymphoid organs (Chen et al, 2015).…”

“…Another study suggests that IKKα not only regulates the homeostasis of Treg cells but also the expansion and effector function of Treg cells (Chen et al, 2015). T cell-specific ablation of IKKα causes more than 60% reduction in the number of Tregs in both the thymus and the peripheral lymphoid organs (Chen et al, 2015). Furthermore, the IKKα-deficient Tregs are impaired in expansion and effector function when adoptively transferred into Rag1 knockout mice.…”