Retinal self-antigen induces a predominantly Th1 effector response in Axl and Mertk double-knockout mice.
Retinal self-antigen induces a predominantly Th1 effector response in Axl and Mertk double-knockout mice.
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DOI：
10.4049/jimmunol.1101201
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发表时间：
2011-10-15
期刊：
影响因子：
--
通讯作者：
Lu Q
中科院分区：
文献类型：
--
作者：
Ye F;Han L;Lu Q;Dong W;Chen Z;Shao H;Kaplan HJ;Li Q;Lu Q
TAM受体家族（Tyro 3、Axl和Mertk）在DC和巨噬细胞对病原性刺激的应答的负调节中起重要作用，并且缺乏该受体家族的小鼠产生针对多种组织（包括视网膜）的自发性狼疮样系统性自身免疫。为了研究TAM调节APC功能的分子机制以及随后对诱导针对眼睛的自身免疫应答的影响，我们检查了视网膜自身抗原免疫后的CD 4 T细胞分化。从幼稚或感光细胞间类维生素A结合蛋白（IRBP）1-20免疫的Axl和Mertk双敲除（dko）小鼠制备的CD 4 T细胞对使用抗CD 3和抗CD 28抗体的活化反应或对体外自身抗原的支持反应，主要是Th 1效应应答，其特征在于IFN-γ产生增加和IFN-γ阳性CD 4 T细胞的频率更高。如通过ELISA测量培养基中的IL-17 A和分泌IL-17 A的CD 4 T细胞的流式细胞术分析所示，dko小鼠中对IRBP免疫的Th 17效应子应答与WT对照中的相似。有趣的是，从IRBP免疫的dko小鼠中分离的APC或DC表现出更大的驱动Th 1应答的能力。在dko DC和巨噬细胞中，Th 1分化的两种驱动细胞因子IL-12和IL-18的产生显著增加，并且LPS刺激支持它们的产生。在dko小鼠中优先发展成Th 1亚群表明，由突变小鼠在体内或由突变APC在体外产生的细胞因子环境选择性地产生有利于Th 1效应应答的分化环境。
TAM family of receptors (Tyro3, Axl, and Mertk) plays an important role in the negative regulation of response of DCs and macrophages to pathogenic stimuli and mice lacking this receptor family develop spontaneous lupus-like systemic autoimmunity against a variety of tissues, including retina. To study the molecular mechanism underlying the TAM regulation of APC functions and subsequent effects on the induction of an autoimmune response against the eye, we examined CD4 T cell differentiation following retinal self-antigen immunization. CD4 T cells prepared from naïve or interphotoreceptor retinoid-binding protein (IRBP)1-20-immunized Axl and Mertk double knockout (dko) mice reacted to activation using anti-CD3 and anti-CD28 antibodies or to bolster by self-antigen in vitro with a predominantly Th1 effector response, as characterized by increased IFN-γ production and higher frequency of IFN-γ-positive CD4 T cells. The Th17 effector response to IRBP immunization was similar in dko mice to that in WT controls, as shown by ELISA measurement of IL-17A in the culture medium and flow cytometric analysis of IL-17A-secreting CD4 T cells. Interestingly, APCs or DCs isolated from IRBP-immunized dko mice exhibited a greater ability to drive the Th1 response. The production of two driving cytokines for Th1 differentiation, IL-12 and IL-18, was dramatically increased in dko DCs and macrophages, and LPS stimulation bolstered their production. The preferential development into the Th1 subset in dko mice suggests that the cytokine milieu produced by the mutant mice in vivo or by mutant APCs in vitro selectively creates a differentiation environment favoring the Th1 effector response.
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