T Cell and Dendritic Cell Abnormalities Synergize to Expand Pro-Inflammatory T Cell Subsets Leading to Fatal Autoimmunity in B6.NZBc1 Lupus-Prone Mice

We have previously shown that B6 congenic mice with a New Zealand Black chromosome 1 (c1) 96-100 cM interval produce anti-nuclear Abs and that at least two additional genetic loci are required to convert this subclinical disease to fatal glomerulonephritis in mice with a c1 70-100 cM interval (c1(70-100)). Here we show that the number of T follicular helper and IL-21-, IFN-γ-, and IL-17-secreting CD4+ T cells parallels disease severity and the number of susceptibility loci in these mice. Immunization of pre-autoimmune mice with OVA recapitulated these differences. Differentiation of naïve T cells in-vitro under polarizing conditions and in-vivo following adoptive transfer of OVA-specific TCR transgenic cells into c1(70-100) or B6 recipient mice, revealed T cell functional defects leading to increased differentiation of IFN-γ- and IL-17-producing cells in the 96-100 cM and 88-96 cM intervals, respectively. However, in-vivo enhanced differentiation of pro-inflammatory T cell subsets was predominantly restricted to c1(70-100) recipient mice, which demonstrated altered dendritic cell function, with increased production of IL-6 and IL-12. The data provide support for the role of pro-inflammatory T cells in the conversion of subclinical disease to fatal autoimmunity and highlight the importance of synergistic interactions between individual susceptibility loci in this process.

我们此前已证实，携带新西兰黑品系1号染色体（New Zealand Black chromosome 1, c1）96-100 cM区间的C57BL/6（B6）同源导入小鼠（congenic mice）可产生抗核抗体；对于携带c1 70-100 cM区间（c1(70-100)）的小鼠而言，至少还需两个额外的遗传位点，才能将该亚临床疾病进展为致死性肾小球肾炎。本研究发现，滤泡辅助性T细胞（T follicular helper）以及分泌白细胞介素21（IL-21）、干扰素γ（IFN-γ）和白细胞介素17（IL-17）的CD4阳性T细胞（CD4+ T cells）的数量，与这类小鼠的疾病严重程度及易感遗传位点数量呈正相关。对自身免疫前期小鼠进行卵清蛋白（OVA）免疫，可重现上述差异。在极化诱导条件下体外诱导初始T细胞（naïve T cells）分化，以及将卵清蛋白特异性T细胞受体转基因细胞（TCR transgenic cells）过继转移（adoptive transfer）至c1(70-100)或B6受体小鼠体内的体内实验均显示，T细胞存在功能缺陷，分别导致96-100 cM区间和88-96 cM区间小鼠中分泌干扰素γ和白细胞介素17的细胞分化程度升高。然而，促炎性T细胞亚群的体内增强分化主要局限于c1(70-100)受体小鼠；这类小鼠表现出树突状细胞（dendritic cell）功能异常，且白细胞介素6（IL-6）和白细胞介素12（IL-12）的产生量显著升高。本研究数据证实了促炎性T细胞在亚临床疾病进展为致死性自身免疫病过程中的关键作用，并凸显了单个易感遗传位点之间的协同互作在该进程中的重要意义。