Impairment of Regulatory Capacity of CD4+CD25+ Regulatory T Cells Mediated by Dendritic Cell Polarization and Hyperthyroidism in Graves' Disease
Impairment of Regulatory Capacity of CD4+CD25+ Regulatory T Cells Mediated by Dendritic Cell Polarization and Hyperthyroidism in Graves' Disease
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DOI：
10.4049/jimmunol.0904135
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发表时间：
2011-04-15
影响因子：
4.4
通讯作者：
Zhang, Yanyun
中科院分区：
文献类型：
--
作者：
Mao, Chaoming;Wang, Shu;Zhang, Yanyun
Graves病（GD）是最常见的自身免疫性疾病之一。GD中的免疫功能障碍涉及促甲状腺激素受体（TSHR）自身抗体的产生，其可能是由于树突状细胞（DC）、T细胞和调节性T（Treg）细胞之间的相互作用而产生的。然而，它们之间的相互作用，导致这种自身免疫性疾病的诱导和调节的免疫机制是不明确的。在这项研究中，我们调查了DC是否是GD患者Treg细胞活性缺陷的主要原因。我们发现在未经治疗的GD患者（uGD）中，循环中CD 4（+）CD 25（+）FOXP 3（+）Treg细胞的百分比显著降低，这与TSHR自身抗体的浓度呈负相关。uGD衍生的DC被极化以增加浆细胞样DC（pDC）的数量，并通过以IFN-α依赖性方式诱导CD 4（+）CD 25（+）Treg细胞的凋亡而赋予废除Treg细胞的抑制功能的能力，并且升高的甲状腺激素进一步加剧了该作用。核苷酸UDP通过P2 Y 6受体信号传导抑制pDC的IFN-alpha分泌，恢复了CD 4（+）CD 25（+）Treg细胞的抑制功能。总的来说，通过pDC极化的uGD衍生的DC和升高的甲状腺激素共同作用以损害Treg细胞的调节能力，促进GD发病机制中TSHR自身抗体的产生。免疫学杂志，2011，186：4734-4743。
Graves' disease (GD) is one of the most common autoimmune diseases. The immune dysfunction in GD involves the generation of thyroid-stimulating hormone receptor (TSHR) autoantibodies that presumably arise consequent to interactions among dendritic cells (DCs), T cells, and regulatory T (Treg) cells. However, the immunological mechanisms of interactions between them that lead to the induction and regulation of this autoimmune disease are poorly defined. In this study, we investigated whether DCs are the main cause of the defective activity of Treg cells in GD patients. We found a significant decrease in the percentage of circulating CD4(+)CD25(+)FOXP3(+) Treg cells in untreated GD patients (uGD), which was negatively correlated with the concentration of TSHR autoantibodies. uGD-derived DCs were polarized to increase the number of plasmacytoid DCs (pDCs) and conferred the ability to abrogate the suppressive function of Treg cells through inducing apoptosis of CD4(+)CD25(+) Treg cells in an IFN-alpha-dependent manner, and elevated thyroid hormones further exacerbated the effect. The nucleotide UDP, which inhibits IFN-alpha secretion of pDCs through P2Y6 receptor signaling, restored the suppressive function of CD4(+)CD25(+) Treg cells. Collectively, uGD-derived DCs through pDC polarization and elevated thyroid hormones act in concert to impair the regulatory capacity of Treg cells, facilitating the production of TSHR autoantibodies in the pathogenesis of GD. The Journal of Immunology, 2011, 186: 4734-4743.