Cell-Intrinsic NF-κB Activation Is Critical for the Development of Natural Regulatory T Cells in Mice

Abstract

BackgroundNaturally occurring CD4+CD25+Foxp3+ regulatory T (Treg) cells develop in the thymus and represent a mature T cell subpopulation critically involved in maintaining peripheral tolerance. The differentiation of Treg cells in the thymus requires T cell receptor (TCR)/CD28 stimulation along with cytokine-promoted Foxp3 induction. TCR-mediated nuclear factor kappa B (NF-κB) activation seems to be involved in differentiation of Treg cells because deletion of components of the NF-κB signaling pathway, as well as of NF-κB transcription factors, leads to markedly decreased Treg cell numbers in thymus and periphery.Methodology/Principal FindingsTo investigate if Treg cell-intrinsic NF-κB activation is required for thymic development and peripheral homeostasis of Treg cells we used transgenic (Tg) mice with thymocyte-specific expression of a stable IκBα mutant to inhibit NF-κB activation solely within the T cell lineage. Here we show that Treg cell-intrinsic NF-κB activation is important for the generation of cytokine-responsive Foxp3− thymic Treg precursors and their further differentiation into mature Treg cells. Treg cell development could neither be completely rescued by the addition of exogenous Interleukin 2 (IL-2) nor by the presence of wild-type derived cells in adoptive transfer experiments. However, peripheral NF-κB activation appears to be required for IL-2 production by conventional T cells, thereby participating in Treg cell homeostasis. Moreover, pharmacological NF-κB inhibition via the IκB kinase β (IKKβ) inhibitor AS602868 led to markedly diminished thymic and peripheral Treg cell frequencies.Conclusion/SignificanceOur results indicate that Treg cell-intrinsic NF-κB activation is essential for thymic Treg cell differentiation, and further suggest pharmacological NF-κB inhibition as a potential therapeutic approach for manipulating this process.

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

“…For example, it was reported that c‐Re1 regulates the differentiation of Tregs (28–31). The Ubc13TKKβ signaling axis was shown to promote the maintenance of suppressive function and phenotypic stability of Tregs (32), and IKKβ was also shown to be involved in the generation of Tregs (33). In this study, we found that specific ablation of IKKα in CD4 cells resulted in a marked reduction of Tregs in the thymus as well as in the peripheral lymphoid tissues.…”

miR-146b antagomir–treated human Tregs acquire increased GVHD inhibitory potency

“…49,50 To address the role of NF-kB in human tTregs, an inhibitor of the NF-kB pathway (PS1145) was added for the final 2 days of culture. 51 NF-kB inhibition decreased Foxp3 expression in a dose-dependent manner, leading to significantly decreased in vitro suppressive function ( Figure 5D-G).…”

Curcumin inhibits suppressive capacity of naturally occurring CD4+CD25+ regulatory T cells in mice in vitro

“…One potential pathway downstream of TCR has been suggested to be nuclear factor-κB (NF-κB), as mice deficient in upstream molecules such as protein kinase C θ, Bcl-10, CARMA1, and MALT1 had few Tregs [10]. Moreover, enhancing the signal strength of NF-κB pathway can induce Foxp3 expression in T cells [10,11]. Hence, NF-κB may play a crucial role in regulating Foxp3 expression in Tregs.…”