Lipid-dependent regulation of human Th17 cell function

摘要 Th17细胞是一种产生IL-17的CD4T效应细胞亚群，主要分布在 与许多人类炎症性和自身免疫性疾病有关，源于炎症性肠病 疾病到多发性硬化症。维甲酸孤儿受体γt(rorγt)，一种核激素 受体，编程Th17细胞的发育和功能。其最终目标是调制 炎性T细胞在疾病背景下，我们进行了化学和基因筛查，以 确定驱动人类γ细胞功能的RoR-Th17测试靶基因。有趣的是，我们的结果 在一条新的途径中牵涉到一组基因，该途径将与脂代谢、RoRγt活性联系起来 和Th17细胞的功能。因此，我们将检验Th17细胞功能受控于 很大一部分是由RoRγt靶基因通过脂滴(LDs)(与 脂类代谢)。我们将采取以下方法：首先，我们将确定与学习障碍有关的 基因--具体地说，是HILPDA和BNIP3--是必要的、充分的和特定的调节因子 人类Th17细胞功能正常。第二，我们将阐明LDS的分子机制 调节Th17细胞分化。第三，利用小鼠的自身免疫性疾病模型，我们将 确定LDS在炎症和自身免疫病理中的生理意义。 我们的结果可能有助于揭示控制Th17细胞的新的血脂调节机制 炎症性疾病的反应。

Abstract Th17 cells are an Interleukin-17-producing subset of CD4+ T effector cells that are centrally implicated in many human inflammatory and autoimmune diseases, from inflammatory bowel disease to multiple sclerosis. The retinoid orphan receptor gamma t (RORγt), a nuclear hormone receptor, programs Th17 cell development and function. With the ultimate goal of modulating inflammatory T cells in disease settings, we undertook chemical and genetic screening to identify RORγt target genes that drive human Th17 cell function. Intriguingly, our results implicated a group of genes in a novel pathway that would link lipid metabolism, RORγt activity and Th17 cell functions. We will thus test the hypothesis that Th17 cell function is controlled in large part, by RORγt target genes, via lipid droplets (LDs) (cellular organelles associated with lipid metabolism). We will take the following approaches: First, we will determine if LD- related genes – specifically, HILPDA and BNIP3 – are necessary, sufficient and specific regulators of human Th17 cell functions. Second, we will elucidate the molecular mechanisms by which LDs modulate Th17 cell differentiation. Third, using autoimmune disease models in mice, we will determine the physiological significance of LDs in inflammation and autoimmune pathologies. Our results may shed a light on novel lipid-regulatory mechanisms that control Th17 cell responses in inflammatory diseases.