Regulation of Th17 differentiation by epidermal fatty acid-binding protein.
Regulation of Th17 differentiation by epidermal fatty acid-binding protein.
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DOI：
10.4049/jimmunol.0804192
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发表时间：
2009-06-15
期刊：
影响因子：
--
通讯作者：
Suttles J
中科院分区：
文献类型：
--
作者：
Li B;Reynolds JM;Stout RD;Bernlohr DA;Suttles J
表皮脂肪酸结合蛋白（E-FABP）是一种脂质分子伴侣，可调节巨噬细胞和树突状细胞的炎症功能。在此，我们证明了E-FABP的T细胞表达促进Th 17分化，同时反调节FoxP 3+调节性T细胞（Treg）的发育。与野生型小鼠相比，E-FABP缺陷型小鼠对髓磷脂少突胶质细胞糖蛋白肽（MOG 35 -55）的免疫应答产生了降低水平的Th 17细胞和升高水平的Tcl 3。同样，当分别经受Th 17或Treg极化条件时，从E-FABP缺陷小鼠分离的幼稚CD 4 + T细胞在体外显示IL-17表达降低和FoxP 3表达增强。先前已经证明，由IL-6诱导的IL-21刺激核受体RORγt和RORα的表达，这反过来诱导IL-17的表达。我们发现E-FABP缺陷型CD 4 + T细胞的Th 17分化受损与IL-6应答的IL-21表达水平降低以及RORγt和RORα表达降低相关。然而，E-FABP缺陷型CD 4 + T细胞表达的核受体PPARγ水平显著高于野生型CD 4 + T细胞，并且用PPARγ拮抗剂GW 9662处理使E-FABP缺陷型T细胞的IL-21、RORγt、RORα和IL-17的表达恢复至野生型水平。E-FABP缺乏对IL-17表达的负面影响归因于PPARγ介导的IL-6诱导的STAT 3活性的抑制。因此，综合考虑，我们的数据表明，CD 4 + T细胞表达E-FABP有助于控制IL-21/ROR/IL-17途径的IL-6刺激和Th 17/Treg平衡。
Epidermal fatty acid binding protein, E-FABP, a lipid chaperone, has been shown to regulate the inflammatory function of macrophages and dendritic cells. Herein, we demonstrate that T cell expression of E-FABP promotes Th17 differentiation, while counter-regulating development of FoxP3+ regulatory T cells (Treg). In response to immunization with myelin oligodendrocyte glycoprotein peptide (MOG35–55), E-FABP-deficient mice generated reduced levels of Th17 cells and elevated levels of Tregs, as compared to wild-type mice. Likewise, naïve CD4+ T cells isolated from E-FABP-deficient mice showed reduced expression of IL-17 and enhanced expression of FoxP3, in vitro, when subjected to Th17 or Treg polarizing conditions, respectively. It has been demonstrated previously that IL-21, induced by IL-6, stimulates the expression of the nuclear receptors RORγt and RORα, which in turn induce expression of IL-17. We found that the impaired Th17 differentiation by E-FABP-deficient CD4+ T cells was associated with lower levels of IL-21 expression in response to IL-6, and reduced expression of RORγt and RORα. However, E-FABP-deficient CD4+ T cells expressed significantly higher levels of the nuclear receptor PPARγ than wild-type CD4+ T cells and treatment with the PPARγ antagonist GW9662 restored expression of IL-21, RORγt, RORα and IL-17 by E-FABP-deficient T cells to wild-type levels. The negative influence of E-FABP-deficiency on IL-17 expression was attributed to PPARγ-mediated suppression of IL-6-induced STAT3 activity. Thus, taken together, our data indicate that expression of E-FABP by CD4+ T cells contributes to the control of IL-6 stimulation of the IL-21/ROR/IL-17 pathway and to the Th17/Treg counter-balance.
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