Gr-1+ cells and the response to nematode parasites

描述（由申请人提供）：T辅助2 （Th2）效应细胞，通过Th2细胞因子的产生，可以介导对寄生虫感染的抗性。因此，了解导致其分化的细胞和分子相互作用对于开发促进宿主保护性免疫反应的疗法和疫苗非常重要。我们已经开始研究线虫寄生虫感染小鼠后最初产生的先天反应，以确定可能在促进适应性免疫中重要的细胞群或信号，从而导致产生IL-4的Th2细胞的发展。寄生虫感染后不久引流淋巴结的整体基因表达分析显示趋化因子显著增加，包括MCP-1和CXCR3配体。已知这两种趋化因子都能招募单核细胞和粒细胞。Gr-1是这些细胞群和浆细胞样树突状细胞共有的细胞表面标记物。在接种巴西乳线虫4和16小时后，引流淋巴结的Gr1+细胞明显增加。抗gr -1抗体处理后，巴西巴西虫接种后18 h淋巴组织IFN-y表达显著升高，接种后7 d淋巴组织IL-4表达降低，宿主对其产生抗性。在本研究中，我们将研究Gr1+细胞在体内促进Th2效应细胞发育的功能。具体来说，我们建议鉴定在巴西扁虱免疫应答的早期阶段介导Gr1+细胞向外周淋巴结募集的趋化因子/趋化因子受体。我们还将通过原位检测Gr1+细胞与发育中的Th2细胞的相互作用，阐明Gr1+细胞如何抑制IFN-y升高并促进Th2细胞发育导致宿主耐药的机制。最后，我们将在两种寄生虫模型中讨论Gr1+细胞在brasiliensis和H. polygyrus宿主保护性初级反应和记忆反应中的作用。

DESCRIPTION (provided by applicant): T helper 2 (Th2) effector cells, through Th2 cytokine production, can mediate resistance to helminthic parasite infection. Understanding the cell and molecular interactions that lead to their differentiation is therefore important for the development of therapies and vaccines that promote host protective immune responses. We have begun to examine the innate response that initially develops following infection of mice with nematode parasites to identify cell populations or signals that may be important in promoting adaptive immunity that leads to the developing of IL-4 producing Th2 cells. Global gene expression analyses of draining lymph nodes shortly after parasite infection showed pronounced increases in chemokines, including MCP-1 and CXCR3 ligands. Both chemokines are known to recruit monocytes and granulocytes. Gr-1 is a cell surface marker shared by these cell populations and also plasmacytoid dendritic cells. Draining lymph nodes showed pronounced increases in Gr1+ cells at 4 and 16 hours after inoculation with the intestinal nematode parasite, N. brasiliensis. Treatment with anti-GR-1 antibody caused marked increases in lymph node IFN-y expression at 18 hours after N. brasiliensis inoculation and decreased IL-4 expression and host resistance was observed at 7 days after inoculation. In the proposed studies, we will examine the function of Gr1+ cells in promoting the development of Th2 effector cells in vivo. Specifically, we propose to identify the chemokine/chemokine receptors that mediate the recruitment of Gr1+ cells to the peripheral lymph nodes at early stages of the immune response to N. brasiliensis. We will also elucidate the mechanism of how Gr1+ cells suppress IFN-y elevations and promote Th2 cell development leading to host resistance by examining Gr1+ cell interactions with developing Th2 cells in situ. Finally, we will address in two parasite models, N. brasiliensis and H. polygyrus, the role of Gr1+ cells in the development of the host protective primary and memory response.