Regulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-κB signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-κB signaling through IκB-kinase β (IKKβ) after thymic egress. Mice lacking IKKβ in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3 Tregs. Also, pharmacological IKKβ inhibition reduced Treg numbers in the circulation by ∼50% and downregulated FoxP3 and CD25 expression and STAT5 phosphorylation. In contrast, activated cytotoxic T lymphocytes (CTLs) were resistant to IKKβ inhibition because other pathways, in particular nuclear factor of activated T cells (NFATc1) signaling, sustained their survival and expansion. In a melanoma mouse model, IKKβ inhibition after CTL cross-priming improved the antitumor response and delayed tumor growth. In conclusion, prolonged IKKβ inhibition decimates circulating Tregs and improves CTL responses when commenced after tumor vaccination, indicating that IKKβ represents a druggable checkpoint.

The NFκB transcription factor family facilitates the activation of dendritic cells (DCs) and CD4(+) T helper (Th) cells, which are important for protective adaptive immunity. Inappropriate activation of these immune cells may cause inflammatory disease, and NFκB inhibitors are promising anti-inflammatory drug candidates. Here, we investigated whether inhibiting the NFκB-inducing kinase IKK2 can attenuate crescentic GN, a severe DC- and Th cell-dependent kidney inflammatory disease. Prophylactic pharmacologic IKK2 inhibition reduced DC and Th cell activation and ameliorated nephrotoxic serum-induced GN in mice. However, therapeutic IKK2 inhibition during ongoing disease aggravated the nephritogenic immune response and disease symptoms. This effect resulted from the renal loss of regulatory T cells, which have been shown to protect against crescentic GN and which require IKK2. In conclusion, although IKK2 inhibition can suppress the induction of nephritogenic immune responses in vivo, it may aggravate such responses in clinically relevant situations, because it also impairs regulatory T cells and thereby, unleashes preexisting nephritogenic responses. Our findings argue against using IKK2 inhibitors in chronic GN and perhaps, other immune-mediated diseases.

Experimental nephrotoxic serum nephritis (NTN) is a model for T‐cell–mediated human rapid progressive glomerulonephritis. T‐cell receptor stimulation involves intracellular signaling events that ultimately lead to the activation of transcription factors, such as NF‐κB. We explored the involvement of the NF‐κB components IKK‐2 and NEMO in NTN, by using cell‐specific knockouts of IKK‐2 and NEMO in CD4+ T lymphocytes. Our results demonstrate that although the course of disease was not grossly altered in CD4xIKK2Δ and CD4xNEMOΔ animals, renal regulatory T cells were significantly reduced and T helper (Th)1 and Th17 cells significantly increased in both knockout mouse groups. The expression of the renal cytokines and chemokines IL‐1β, CCL‐2, and CCL‐20 was also significantly altered in both knockout mice. Lymphocyte transcriptome analysis confirmed the increased expression of Th17‐related cytokines in spleen CD4+ T cells. Moreover, our array data demonstrate an interrupted canonical NF‐κB pathway and an increased expression of noncanonical NF‐κB pathway–related genes in nephritic CD4xNEMOΔ mice, highlighting different downstream effects of deletion of IKK‐2 or NEMO in T lymphocytes. We propose that better understanding of the role of IKK‐2 and NEMO in nephritis is essential for the clinical application of kinase inhibitors in patients with glomerulonephritis.—Guo, L., Huang, J., Chen, M., Piotrowski, E., Song, N., Zahner, G., Paust, H.‐J., Alawi, M., Geffers, R., Thaiss, F. T‐lymphocyte–specific knockout of IKK‐2 or NEMO induces Th17 cells in an experimental nephrotoxic nephritis mouse model. FASEB J. 33, 2359–2371 (2019). http://www.fasebj.org