Fcgamma mediated regulation of dendritic cell function

描述(申请人提供)：树突状细胞(DC)是一种特殊的抗原提呈细胞，既可以介导T细胞免疫，也可以介导免疫耐受。向DC传递的特定成熟信号的性质是DC功能的重要决定因素。FC？受体(Fc？R)系统包括激活受体和抑制受体，它们通常在细胞表面共表达。激活和抑制信号之间的平衡决定了免疫复合体介导的炎症和免疫的结果。我们最近的研究表明，选择性地阻断DC上抑制的Fc？R、Fc？RIIb可以激活DC并增强T细胞免疫。这种DC成熟是独特的，其特征是诱导几种趋化因子和细胞因子以及I型干扰素(干扰素)反应基因。我们的初步数据表明，成熟的FC？R树突状细胞具有激活人类产生IL-17的CD4和CD8 T细胞的能力。我们的假设是，FC？R信号平衡影响DC对Th17细胞的诱导。本研究的目的是：1)比较Fc？R激活的DC与炎性细胞因子酵母多糖或肽聚糖成熟的DC诱导的人IL-17产生T细胞的特性。2)探讨活化Fc-Rs及其下游分子在DC介导的Th17-1细胞活化中的作用。3)评价负载调亡肿瘤细胞的DC诱导的Th17-1细胞的抗肿瘤功能。这些研究将有助于我们理解FC的作用？通过对树突状细胞生物学受体的研究，为炎症和疾病以及肿瘤免疫中Fc？R介导的免疫调节提供了新的见解。。公共卫生相关性：树突状细胞(DC)是一种特殊的抗原提呈细胞，介导T细胞的激活。我们以前已经证明，DC的功能可以通过改变其FC？感受器。在本应用程序中，我们将检查FC？受体平衡与DC诱导Th17细胞的能力、诱导Th17细胞的途径以及DC诱导Th17细胞的功能有关。

DESCRIPTION (provided by applicant): Dendritic cells (DCs) are specialized antigen presenting cells that can mediate both T cell immunity as well as immune tolerance. The nature of specific maturation signal delivered to DCs is an important determinant of DC function. Fc? receptor (Fc?R) system includes activating as well as inhibitory receptors that are usually co-expressed on the cell surface. The balance between the activating and inhibitory signals determines the outcome of immune complex mediated inflammation and immunity. We have recently shown that selective blockade of the inhibitory Fc?R, Fc?RIIB on DCs leads to DC activation and enhanced generation of T cell immunity. This DC maturation is distinct and characterized by induction of several chemokines and cytokines as well as type I interferon (IFN) response genes. Our preliminary data suggests that Fc?R matured DCs have the ability to activate IL17 producing CD4 as well as CD8 T cells in humans. Our hypothesis is that the balance of Fc?R signaling impacts induction of Th17 cells by DCs. The aims of this application are I) To compare the properties of human IL17 producing T cells induced by Fc?R activated DCs with those generated by DCs matured with inflammatory cytokines zymosan or peptidoglycan. 2) To evaluate the role of activating Fc?Rs and downstream molecules in DC mediated activation of Th17-1 cells 3) To evaluate the anti-tumor function of the Th17-1 cells induced by DCs loaded with opsonized apoptotic tumor cells. These studies will help us understand the role Fc? receptors on dendritic cell biology and provide novel insights into Fc?R mediated immune regulation in inflammation and disease as well as tumor immunity. . PUBLIC HEALTH RELEVANCE: Dendritic cells (DCs) are specialized antigen presenting cells that mediate activation of T cells. We have previously shown that the function of DCs can be modulated by altering the signaling via their Fc? receptors. In this application we will examine the effect of the modulation of the Fc? receptor balance on the ability of DCs to induce Th17 cells, the pathways involved in the induction of Th17 cells as well as the function of the Th17 cells induced by the DCs.