Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
J Autoimmun. 2019 Mar;98:86-94. doi: 10.1016/j.jaut.2018.12.002. Epub 2019 Jan 5.
CTLA-4 is required for CD4Foxp3 regulatory T (Treg) cell function, but its mode of action remains incompletely defined. Herein we generated Ctla-4Foxp3-Cre mice with Treg cells exclusively expressing a naturally occurring, ligand-independent isoform of CTLA-4 (liCTLA-4) that cannot interact with the costimulatory molecules CD80 and CD86. The mice did not exhibit any signs of effector T cell activation early in life, however, at 6 months of age they exhibited excessive T cell activation and inflammation in lungs. In contrast, mice with Treg cells completely lacking CTLA-4 developed lymphoproliferative disease characterized by multi-organ inflammation early in life. In vitro, Treg cells exclusively expressing liCTLA-4 inhibited CD80 and CD86 expression on dendritic cells (DC). Conversely, Treg cells required the extra-cellular part of CTLA-4 to up-regulate expression of the co-inhibitory molecule PD-L2 on DCs. Transcriptomic analysis of suppressed DCs revealed that Treg cells induced a specific immunosuppressive program in DCs.
CTLA-4 对于 CD4Foxp3 调节性 T（Treg）细胞功能是必需的，但它的作用模式仍不完全明确。在此，我们生成了 Ctla-4Foxp3-Cre 小鼠，其 Treg 细胞特异性表达一种天然存在的、配体非依赖性的 CTLA-4 同工型（liCTLA-4），该同工型不能与共刺激分子 CD80 和 CD86 相互作用。这些小鼠在生命早期并没有表现出任何效应 T 细胞激活的迹象，然而，在 6 个月大时，它们的肺部出现了过度的 T 细胞激活和炎症。相比之下，完全缺乏 CTLA-4 的 Treg 细胞在生命早期就发展为具有多器官炎症特征的淋巴增生性疾病。在体外，特异性表达 liCTLA-4 的 Treg 细胞抑制树突状细胞（DC）上 CD80 和 CD86 的表达。相反，Treg 细胞需要 CTLA-4 的细胞外部分来上调 DC 上共抑制分子 PD-L2 的表达。受抑制的 DC 的转录组分析表明，Treg 细胞在 DC 中诱导了一种特定的免疫抑制程序。
