Altered generation of induced regulatory T cells in the FVB.mdr1a-/- mouse model of colitis.
Altered generation of induced regulatory T cells in the FVB.mdr1a-/- mouse model of colitis.
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缺乏小分子泵P-糖蛋白（P-gp）的FVB.mdr1a−/−小鼠是研究自发性T细胞介导的结肠炎的常用模型。此外，人类的MDR 1多态性和P-gp缺乏与溃疡性结肠炎的发生有关。我们现在证明，P-gp缺陷的小鼠在肠固有层中Foxp 3+调节性T细胞（Treg）的水平降低。这种减少不是由于Treg细胞凋亡增加、Treg运输改变或Treg可塑性增强而成为Foxp 3 +IL-17+细胞。相反，P-gp缺陷似乎限制了诱导Treg细胞（iTreg）的发育，因为在体外TGF-β治疗和过继转移到FVB.rag2−/−受体后，从幼稚FVB.mdr1a−/− T细胞中发育的Foxp 3 + iTreg较少。相反，体外TGF-β处理导致IL-17+ CD 4 + T细胞。这种iTribunal发育的失败解释了FVB.mdr1a−/−肠道中Foxp 3 + Tribunal的减少，这表明需要在具有MDR 1多态性的人类炎症性肠病患者中研究这种新的疾病机制。
The FVB.mdr1a−/− mouse, lacking the small molecule pump P-glycoprotein (P-gp), is a commonly used model for the study of spontaneous T cell mediated colitis. In addition, MDR1 polymorphisms and P-gp deficiency in humans have been linked to the development of ulcerative colitis. We now demonstrate that mice with P-gp deficiency have decreased levels of Foxp3+ regulatory T cells (Treg) in the intestinal lamina propria. This decrease is not due to either increased Treg apoptosis, altered Treg trafficking, or enhanced Treg plasticity to become Foxp3+IL-17+ cells. Instead, P-gp deficiency appears to restrict the development of induced Treg cells (iTreg), as fewer Foxp3+ iTregs developed from naïve FVB.mdr1a−/− T cells both upon TGF-β treatment in vitro and after adoptive transfer into FVB.rag2−/− recipients. Rather, in vitro TGF-β treatment results in a IL-17+CD4+ T cell. This failure of iTregs to develop explains the decrease in Foxp3+ Tregs in the FVB.mdr1a−/− intestine, representing a need to investigate this novel disease mechanism in human inflammatory bowel disease patients with MDR1 polymorphisms.
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