Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4(+)CD45RC- cells and CD4(+)CD8(-) thymocytes.
Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4(+)CD45RC- cells and CD4(+)CD8(-) thymocytes.
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DOI：
10.1084/jem.189.2.279
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发表时间：
1999-01-18
影响因子：
15.3
通讯作者：
Mason, D
中科院分区：
文献类型：
--
作者：
Seddon, B;Mason, D
先前的研究表明，PVG.RT1u大鼠的成年胸腺切除术和分次剂量照射诱导的自身免疫性糖尿病可以通过与来自正常同基因供体的外周CD 4 + CD 45 RC −TCR-α/β+ RT 6+细胞和CD 4 + CD 8 −胸腺细胞重建来预防。这些数据为调节性T细胞在预防组织特异性自身免疫性疾病中的作用提供了证据，但这些细胞的作用方式以前尚未报道。在这项研究中，使用类似的胸腺切除术和照射方案在PVG.RT1c大鼠中诱导自身免疫性甲状腺炎。尽管细胞介导的机制与PVG.RT1u大鼠糖尿病的发病机制有关，但甲状腺炎的发生不依赖于CD 8 + T细胞，其特征在于高滴度的免疫球蛋白（IG）G1抗甲状腺球蛋白抗体，表明疾病发病机制中的主要体液成分。与PVG.RT1u大鼠的自身免疫性糖尿病一样，甲状腺炎的发生可以通过正常供体的CD 4 + CD 45 RC −和CD 4 + CD 8 −胸腺细胞的转移来预防，但不能通过CD 4 + CD 45 RC+外周T细胞来预防。我们现在表明，转化生长因子（TGF）-β和白细胞介素（IL）-4在这种保护机制中发挥着重要作用，因为给予阻断这些细胞因子之一的生物活性的单克隆抗体会消除供体细胞的保护作用受体大鼠。因此，CD 4 + CD 45 RC −外周细胞和CD 4 + CD 8 −胸腺细胞对糖尿病和甲状腺炎的预防并不支持调节机制涉及从T辅助细胞1型（Th 1）向Th 2样应答的转变的观点，而是依赖于对涉及TGF-β和IL-4的自身免疫应答的特异性抑制。无论是胸腺细胞还是外周细胞用于预防自身免疫，相同的两种细胞因子参与保护机制的观察结果强烈表明，来自两种来源的调节细胞以相同的方式起作用，并且胸腺细胞在外周中被编程以发挥其保护作用。这一结果与免疫稳态的影响进行了讨论。
Previous studies have shown that induction of autoimmune diabetes by adult thymectomy and split dose irradiation of PVG.RT1u rats can be prevented by their reconstitution with peripheral CD4+CD45RC−TCR-α/β+RT6+ cells and CD4+CD8− thymocytes from normal syngeneic donors. These data provide evidence for the role of regulatory T cells in the prevention of a tissue-specific autoimmune disease but the mode of action of these cells has not been reported previously. In this study, autoimmune thyroiditis was induced in PVG.RT1c rats using a similar protocol of thymectomy and irradiation. Although a cell-mediated mechanism has been implicated in the pathogenesis of diabetes in PVG.RT1u rats, development of thyroiditis is independent of CD8+ T cells and is characterized by high titers of immunoglobulin (Ig)G1 antithyroglobulin antibodies, indicating a major humoral component in the pathogenesis of disease. As with autoimmune diabetes in PVG.RT1u rats, development of thyroiditis was prevented by the transfer of CD4+CD45RC− and CD4+CD8− thymocytes from normal donors but not by CD4+CD45RC+ peripheral T cells. We now show that transforming growth factor (TGF)-β and interleukin (IL)-4 both play essential roles in the mechanism of this protection since administration of monoclonal antibodies that block the biological activity of either of these cytokines abrogates the protective effect of the donor cells in the recipient rats. The prevention of both diabetes and thyroiditis by CD4+CD45RC− peripheral cells and CD4+CD8− thymocytes therefore does not support the view that the mechanism of regulation involves a switch from a T helper cell type 1 (Th1) to a Th2-like response, but rather relies upon a specific suppression of the autoimmune responses involving TGF-β and IL-4. The observation that the same two cytokines were implicated in the protective mechanism, whether thymocytes or peripheral cells were used to prevent autoimmunity, strongly suggests that the regulatory cells from both sources act in the same way and that the thymocytes are programmed in the periphery for their protective role. The implications of this result with respect to immunological homeostasis are discussed.