TCDD-treated B Cells Modulate T Effector and T Regulatory Function in EAE

摘要 2，3，78-四氯二苯并对二恶英(TCDD)抑制免疫的机制研究 这很重要，有几个原因。首先，长期低剂量接触TCDD有可能产生 免疫毒性，并使人群更容易感染疾病。第二，TCDD可以作为模型配体 了解淋巴细胞芳香烃受体(AHR)信号转导途径。最后，AHR配体的鉴定 比TCDD产生的全身毒性更小的药物可能会导致对自身免疫和 炎症性疾病。我们已经证实，亚慢性低剂量TCDD产生抑制 实验性自身免疫性脑脊髓炎(EAE)的效应T细胞功能与疾病的缓解 多发性硬化症的动物模型。我们确定TCDD不仅抑制T细胞细胞因子的产生 而且还能诱导调节性T细胞(Tregs)。这项研究提案的目标是确定 TCDD对EAE调节性B细胞群的影响及TCDD治疗调节性B细胞的作用 细胞对TCDD介导的T细胞功能的改变起作用。我们将检验这一假设，即 TCDD通过诱导调节细胞来抑制EAE，该调节细胞控制效应器和 调节性T细胞反应。我们的第一个具体目标(SA)将是表征TCDD对 调节性B细胞群，重点是可以通过细胞-细胞改变T细胞功能的调节性B细胞 互动。我们的第二个SA是确定TCDD处理的B调节细胞对TH1、TH2的作用 和TH17效应T细胞。我们的第三个SA是确定TCDD处理的B调节细胞在 特雷格斯。我们期望这些研究的结果将证实TCDD可以诱导调节性B细胞 有助于抑制效应器T细胞反应或诱导Tregs的群体。这些研究 还将对TCDD在小鼠和人类体内诱导调节性B细胞的能力进行比较。 这项研究提案的另一个关键方面是，几名本科生将参与到 为期3年，接受假设检验、实验设计、数据分析和 口译，并以口头和书面形式有效传播成果。

ABSTRACT Determination of the mechanisms by which 2,3,78-tetrachlorodibenzo-p-dioxin (TCDD) suppress immunity are important for several reasons. First, there is potential for chronic low dose TCDD exposure to produce immunotoxicity and render populations susceptible to disease. Second, TCDD can be used as a model ligand to understand aryl hydrocarbon receptor (AHR) signaling in lymphocytes. Finally, identification of AHR ligands that produce less systemic toxicity than TCDD might lead to useful therapeutics for autoimmune and inflammatory diseases. We have established that subchronic low dose TCDD produced suppression of effector T cell function and attenuation of disease in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We determined that TCDD not only suppressed T cell cytokine production but also induced regulatory T cells (Tregs). The goal of this research proposal is to determine the effect of TCDD on regulatory B cell populations in EAE and assess the contribution that TCDD-treated regulatory B cells make to TCDD-mediated alterations in T cell function. We will test the hypothesis that the mechanism by which TCDD suppresses EAE involves induction of regulatory cells, which control effector and regulatory T cell responses. Our first specific aim (SA) will be to characterize the effects of TCDD on regulatory B cell populations with a focus on regulatory B cells that can alter T cell function through cell-cell interactions. Our second SA is to determine the role that TCDD-treated B regulatory cells have on TH1, TH2 and TH17 effector T cells. Our third SA is to determine the role that TCDD-treated B regulatory cells have on Tregs. We expect that the results from these studies will establish that TCDD can induce regulatory B cell populations that contribute to either suppression of effector T cell responses or induction of Tregs. The studies will also provide a comparison of the ability of TCDD to induce regulatory B cells in mouse and human. Another critical aspect of this research proposal is that several undergraduate students will be involved over the 3-year period and receive training in hypothesis testing, experimental design, data analysis and interpretation, and effective dissemination of results in both oral and written form.