Mast Cell Function in Protective And Pathological Immunity: A Role for MDSC?

描述（由申请人提供）：肥大细胞是先天免疫和适应性免疫的关键激活剂。尽管肥大细胞在过敏性疾病中的作用最为人所知，但它们能迅速识别细菌和寄生虫病原体。ige介导的信号是肥大细胞激活的最佳途径，我们发现这一途径可以快速诱导Stat5的功能。这种转录因子的缺失极大地破坏了肥大细胞的功能，包括迁移和细胞因子的产生。这一提议将验证ige介导的信号通过Fyn激酶介导的途径激活Stat5，并通过鞘氨酸激酶前馈增强的假设。我们还描述了肥大细胞和髓源性抑制细胞（MDSC）之间的一种新的相互作用，这种相互作用诱导MDSC产生炎症细胞因子，与这些细胞普遍接受的作用相反。我们假设这种作用需要MDSC中的Stat3和Stat5信号，并支持肥大细胞-MDSC相互作用用于驱逐Nippostrongylus寄生虫的理论。我们的建议将验证肥大细胞和MDSC相互作用控制保护性和病理性免疫的假设，这些活动与Stat5信号传导有关。我们将通过体外机制实验和体内功能分析来验证这一假设。我们的具体目的是：1 .验证IgE通过鞘氨酸激酶增强的fyn介导途径激活Stat5A和Stat5B的假设。2。为了验证肥大细胞调节MDSC功能的假设。！

DESCRIPTION (provided by applicant): Mast cells are critical activators of innate and adaptive immunity. Although best known for their role in allergic disease, mast cells rapidly recognize bacterial and parasitic pathogens. IgE-mediated signaling is the best-studied pathway for mast cell activation - a pathway we show rapidly induces Stat5 function. Loss of this transcription factor greatly disrupts mast cell functions, including migration and cytokine production. This proposal will test the hypothesis that IgE-mediated signaling activates Stat5 via a Fyn kinase-mediated pathway with feed-forward augmentation by sphingosine kinase. We also describe a novel interaction between mast cells and myeloid derived suppressor cells (MDSC) that induces MDSC to produce inflammatory cytokines, contrary to the commonly-accepted role of these cells. We postulate that Stat3 and Stat5 signaling in MDSC is required for this effect, and support the theory that mast cell-MDSC interactions are needed for expelling the parasite Nippostrongylus. Our proposal will test the hypothesis that mast cells and MDSC interactions control protective and pathological immunity, activities that are linked by Stat5 signaling. We will test this hypothesis with mechanistic experiments in vitro and functional assays in vivo. Our Specific Aims are: I. To test the hypothesis that IgE activates Stat5A and Stat5B through a Fyn-mediated pathway augmented by sphingosine kinase. II. To test the hypothesis that mast cells regulate MDSC function. !