The maintenance of regulatory T (T_reg) cells critically prevents autoimmunity. Pre–B cell leukemia transcription factor 1 (Pbx1) variants are associated with lupus susceptibility, particularly through the expression of a dominant negative isoform Pbx1-d in CD4⁺ T cells. Pbx1-d overexpression impaired T_reg cell homeostasis and promoted inflammatory CD4⁺ T cells. Here, we showed a high expression of Pbx1 in human and murine T_reg cells, which is decreased in lupus patients and mice. Pbx1 deficiency or Pbx1-d overexpression reduced the number, stability, and suppressive activity of T_reg cells, which increased murine responses to immunization and autoimmune induction. Mechanistically, Pbx1 deficiency altered the expression of genes implicated in cell cycle and apoptosis in T_reg cells. Intriguingly, Rtkn2, a Rho-GTPase previously associated with T_reg homeostasis, was directly transactivated by Pbx1. Our results suggest that the maintenance of T_reg cell homeostasis and stability by Pbx1 through cell cycle progression prevent the expansion of inflammatory T cells that otherwise exacerbates lupus progression in the hosts.

中文翻译：

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狼疮易感基因 Pbx1 通过 Rtkn2 表达控制调节性 T 细胞的发育、稳定性和功能

_{调节性 T (T reg} ) 细胞的维持对于预防自身免疫至关重要。前 B 细胞白血病转录因子 1 ( Pbx1 ) 变异与狼疮易感性相关，特别是通过CD4 ⁺ T 细胞中显性失活亚型Pbx1-d的表达。Pbx1-d过度表达会损害 T _reg细胞稳态并促进炎症性 CD4 ⁺ T 细胞。在这里，我们发现Pbx1在人类和小鼠 T _reg细胞中高表达，而在狼疮患者和小鼠中表达降低。Pbx1缺乏或Pbx1-d过度表达会降低 T _reg细胞的数量、稳定性和抑制活性，从而增加小鼠对免疫和自身免疫诱导的反应。从机制上讲，Pbx1缺陷改变了 T _reg细胞中与细胞周期和凋亡有关的基因的表达。有趣的是，Rtkn2 （一种先前与 T _reg稳态相关的 Rho-GTP 酶）可直接被 Pbx1 反式激活。我们的结果表明，Pbx1通过细胞周期进展维持 T _reg细胞稳态和稳定性，可防止炎症 T 细胞的扩张，否则会加剧宿主狼疮的进展。