Institute of Experimental Immunology, Rheinische Friedrich-Wilhelms-Universität, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
III. Medizinische Klinik, Universitätsklinikum Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Cell Rep. 2017 Oct 17;21(3):578-586. doi: 10.1016/j.celrep.2017.09.082.
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.
调节性 T 细胞（Tregs）可预防自身免疫，但会限制抗肿瘤免疫。经典的 NF-κB 信号通路既能激活免疫，又能促进胸腺 Treg 发育。在这里，我们报告成熟的 Tregs 在离开胸腺后仍需要通过 IκB 激酶β（IKKβ）进行 NF-κB 信号转导。在成熟 Tregs 中缺乏 IKKβ 的小鼠由于外周 FoxP3 Tregs 的死亡而发展出类 scurfy 的免疫病理学。此外，药理学 IKKβ 抑制通过减少循环中 Treg 的数量约 50%，并下调 FoxP3 和 CD25 的表达和 STAT5 的磷酸化来实现。相比之下，激活的细胞毒性 T 淋巴细胞（CTLs）对 IKKβ 抑制具有抗性，因为其他途径，特别是激活 T 细胞的核因子（NFATc1）信号通路，维持它们的存活和扩增。在黑色素瘤小鼠模型中，CTL 交叉呈递后进行 IKKβ 抑制可改善抗肿瘤反应并延迟肿瘤生长。总之，延长 IKKβ 抑制可破坏循环中的 Tregs，并在肿瘤疫苗接种后开始时改善 CTL 反应，表明 IKKβ 代表了一个可成药的检查点。
