Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis
Functional study of CD4+CD25+ regulatory T cells in health and autoimmune hepatitis
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DOI：
10.4049/jimmunol.176.7.4484
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发表时间：
2006-04-01
影响因子：
4.4
通讯作者：
Yun Ma
中科院分区：
文献类型：
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作者：
Longhi, Maria Serena;Hussain, Munther J.;Yun Ma
在自身免疫性肝炎(AIII)中，调节性CD4(+)CD25(+)T细胞在数量和功能上都存在缺陷。我们利用Transwell实验研究并比较了Tregs在健康受试者和AIH患者中的作用机制。在Transwell实验中，Tregs直接与靶细胞接触或通过半透膜与靶细胞分离培养。我们还研究了Treg FOXP3的表达及其对细胞凋亡的影响。在患者和对照组中，Tregs需要直接接触才能抑制CD4(+)CD25(-)和CD8(+)T细胞的增殖和产生干扰素-γ。此外，在这两种情况下，Treg与其靶标直接接触会导致调节性细胞因子IL-4、IL-10和TGF-β的分泌增加，这表明了一种连锁免疫抑制的机制。Tregs/CD4(+)CD25(-)T细胞共培养导致患者和对照组干扰素-γ和IL-10分泌的变化相似，而转化生长因子-β的分泌增加在患者组明显较低。相反，在患者中，Tregs/CD8(+)T细胞共培养导致IL-4分泌增加。在AIII中，Treg FOXP3的表达低于正常人。在患者和对照组中，FOXP3的表达也存在于CD4(+)CD25(-)T细胞中，尽管表达水平较低，且与抑制功能无关。在患者和对照组中，Tregs的加入不影响靶细胞的凋亡，但在AIH中，CD4(+)CD25(-)T细胞的自发凋亡减少。总而言之，Tregs通过改变细胞因子谱而不是诱导细胞凋亡，通过与靶细胞直接接触来发挥作用。CD_4~(+)、CD_(25)~(-)T细胞自发凋亡缺陷可能参与自身免疫的发生发展。
Regulatory CD4(+)CD25(+) T cells (Tregs) are defective numerically and functionally in autoimmune hepatitis (AIII). We have investigated and compared the mechanism of action of Tregs in healthy subjects and in AIH patients using Transwell experiments, where Tregs are cultured either in direct contact with or separated from their targets by a semipermeable membrane. We also studied Treg FOXP3 expression and effect on apoptosis. Direct contact is necessary for Tregs to suppress proliferation and IFN-gamma production by CD4(+)CD25(-) and CD8(+) T cells in patients and controls. Moreover, in both, direct contact of Tregs with their targets leads to increased secretion of regulatory cytokines IL-4, IL-10, and TGF-beta, suggesting a mechanism of linked immunosuppression. Tregs/CD4(+)CD25(-) T cell cocultures lead to similar changes in IFN-gamma and IL-10 secretion in patients and controls, whereas increased TGF-beta secretion is significantly lower in patients. In contrast, in patients, Tregs/CD8(+) T cell cocultures lead to a higher increase of IL-4 secretion. In AIII, Treg FOXP3 expression is lower than in normal subjects. Both in patients and controls, FOXP3 expression is present also in CD4(+)CD25(-) T cells, although at a low level and not associated to suppressive function. Both in patients and controls, addition of Tregs does not influence target cell apoptosis, but in AIH, spontaneous apoptosis of CD4(+)CD25(-) T cells is reduced. In conclusion, Tregs act through a direct contact with their targets by modifying the cytokine profile and not inducing apoptosis. Deficient CD4(+)CD25(-) T cell spontaneous apoptosis may contribute to the development of autoimmunity.