Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
Kidney Int. 2012 Nov;82(9):969-79. doi: 10.1038/ki.2012.242. Epub 2012 Jul 4.
In systemic lupus erythematosus, CD4+ T cells play key roles in the initiation and promotion of autoantigen-specific humoral immunity, and indirect evidence suggests that T cells are pathogenic effectors in lupus nephritis. The contribution of kidney-infiltrating T cells to nephritis, however, has not been verified because of the difficulty in directly analyzing organ-infiltrating T cells. Here, we examined the pathogenic roles of autoreactive cytokine-expressing CD4+ T cells from the kidneys of early nephritic MRL/lpr mice. Interferon (IFN)-γ-secreting cells were enriched among CD5(high)CD4+ T cells found in the inflamed kidneys. Using single-cell analysis of the T-cell receptor (TCR)(high)CD5(high)CD4+ T cells from the kidneys of early nephritic MRL/lpr mice, two IFN-γ-expressing CD4+ T cell clones, MLK2 and MLK3, were identified. CD4+ T cells transduced with the T-cell receptor genes from each clone responded to splenic dendritic cells in an MHC class II-dependent manner, but not to B cells or macrophages. MLK3-transduced CD4+ T cells proliferated in the spleens of prenephritic mice, promoted nephritis progression upon adoptive transfer, and enhanced the deposition of C3 without promoting anti-double-stranded DNA antibody production. Thus, CD4+ T cells in the inflamed kidneys of MRL/lpr mice contribute to nephritis progression.
在系统性红斑狼疮中，CD4+T 细胞在启动和促进自身抗原特异性体液免疫中发挥关键作用，间接证据表明 T 细胞是狼疮肾炎中的致病性效应物。然而，由于直接分析器官浸润 T 细胞存在困难，因此尚未证实浸润肾脏的 T 细胞对肾炎的贡献。在这里，我们研究了来自早期肾炎 MRL/lpr 小鼠肾脏的自身反应性细胞因子表达 CD4+T 细胞的致病作用。在炎症肾脏中发现的 CD5(high)CD4+T 细胞中富含干扰素 (IFN)-γ 分泌细胞。使用早期肾炎 MRL/lpr 小鼠肾脏的 TCR(high)CD5(high)CD4+T 细胞的单细胞分析，鉴定出两个 IFN-γ 表达的 CD4+T 细胞克隆，MLK2 和 MLK3。转导每个克隆的 T 细胞受体基因的 CD4+T 细胞以 MHC 类 II 依赖性方式对脾树突状细胞作出反应，但不与 B 细胞或巨噬细胞反应。MLK3 转导的 CD4+T 细胞在预肾炎小鼠的脾脏中增殖，通过过继转移促进肾炎进展，并增强 C3 的沉积，而不促进抗双链 DNA 抗体的产生。因此，MRL/lpr 小鼠炎症肾脏中的 CD4+T 细胞有助于肾炎进展。
