Centre for Personalised Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
Translational Research Unit, The Canberra Hospital, Canberra, ACT, Australia.
Nat Commun. 2024 Mar 25;15(1):2345. doi: 10.1038/s41467-024-45870-3.
Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Foxp3+ regulatory T cells (Tregs). By contrast, we know very little about the consequences of defects that amplify aspects of Treg function or differentiation. Here we show that mice heterozygous for an Ikbkb gain-of-function mutation develop psoriasis. Doubling the gene dose (Ikbkb) results in dactylitis, spondylitis, and characteristic nail changes, which are features of psoriatic arthritis. Ikbkb mice exhibit a selective expansion of Foxp3 + CD25+ Tregs of which a subset express IL-17. These modified Tregs are enriched in both inflamed tissues, blood and spleen, and their transfer is sufficient to induce disease without conventional T cells. Single-cell transcriptional and phenotyping analyses of isolated Tregs reveal expansion of non-lymphoid tissue (tissue-resident) Tregs expressing Th17-related genes, Helios, tissue-resident markers including CD103 and CD69, and a prominent NF-κB transcriptome. Thus, IKK2 regulates tissue-resident Treg differentiation, and overactivity drives dose-dependent skin and systemic inflammation.
功能丧失突变为 Foxp3+调节性 T 细胞（Tregs）的免疫调节作用提供了重要的见解。相比之下，我们对增强 Treg 功能或分化方面的缺陷的后果知之甚少。在这里，我们发现 Ikbkb 功能获得性突变杂合子的小鼠会发展为银屑病。该基因剂量增加一倍（Ikbkb）会导致指（趾）炎、脊椎炎和特征性指甲变化，这些都是银屑病关节炎的特征。Ikbkb 小鼠表现出 Foxp3+CD25+Treg 的选择性扩增，其中一部分表达 IL-17。这些经过修饰的 Treg 不仅在炎症组织、血液和脾脏中富集，而且其转移足以在没有传统 T 细胞的情况下诱导疾病。分离的 Treg 的单细胞转录组和表型分析显示，表达与 Th17 相关基因、Helios 的非淋巴组织（组织驻留）Treg 扩增，包括 CD103 和 CD69 在内的组织驻留标志物，以及突出的 NF-κB 转录组。因此，IKK2 调节组织驻留 Treg 的分化，过度活跃导致剂量依赖性的皮肤和全身炎症。
