Investigations on antigen-dependent and -independent functions of distinct myeloid subsets of phagocytes in host defence and maintenance of self-tolerance during infection and inflammation

免疫系统使用各种先天的和适应性的(抗原特异的)效应器模式来保护宿主免受病原体入侵。这些免疫防御是有效的，可能会对宿主组织造成实质性损害，需要一系列分层和相互交织的控制机制来限制感染期间和感染后的这种附带损害。这种控制的一个关键部位是在炎症组织损伤期间向适应性免疫系统细胞递送抗原的水平，此时免疫系统必须履行两项相互竞争的义务-通过微生物抗原的免疫递呈促进有效的抗病原体反应，并通过避免这种免疫原性展示自身抗原来限制抗自身反应。申请人最近的工作表明，用于实现这一目的的一个主要机制涉及吞噬细胞亚群(髓细胞)的特化，这样炎性巨噬细胞优先获得和呈现病原体来源的物质，而另一组非免疫原性吞噬细胞则吸收和处置组织碎片。这些细胞类型的特定活动也通过限制免疫原性炎性吞噬细胞亚群摄取自身成分的脂质介体在细胞亚群之间协调。在这项提案中，我详细介绍了在细胞和分子水平上扩展这些初步观察的计划，(1)更彻底地定义不同部位不同髓系细胞在不同部位和不同感染和炎症条件下参与组织清除和抗病原体效应器反应启动的二分性活动的特定作用，(2)确定支持这些不同功能的受体和信号机制，以及(3)通过交叉调节连接定义这些细胞的综合功能。当把这些研究放在其他增强免疫稳态的机制的大背景下，如调节性T细胞、抑制性受体的反馈表达、中枢和外周缺失机制等，这些研究的结果将有助于识别调节装置的部件，其故障可能导致自身免疫性疾病，并为未来的治疗努力提供靶点。

The immune system uses a variety of innate and adaptive (antigen-specific) effector modalities to protect the host against pathogen invasion. These immune defenses are potent and can cause substantial damage to host tissues, requiring a layered and interwoven array of control mechanisms to limit such collateral damage during and after infection. A key locus of such control is at the level of antigen presentation to cells of the adaptive immune system during periods of inflammatory tissue damage, when the immune system must meet two competing obligations - to promote an effect anti-pathogen response through immunogenic presentation of microbial antigens and limit anti-self responses by avoiding such immunogenic display of self-antigens. In recent work from the applicant, it was demonstrated that a major mechanism used to achieve this end involves the specialization of subsets of phagocytes (myeloid cells), such that inflammatory macrophages preferentially acquire and present pathogen-derived over self-derived material, while another population of non-immunogenic phagocytes takes up and disposes tissue debris. These cell-type specific activities are also coordinated between the cell subsets via lipid mediators that limit uptake of self-components by the immunogenic inflammatory phagocyte subset. In this proposal I detail plans for extending these initial observations at the cell and molecular levels, (1) defining more thoroughly the subset specific role of distinct myeloid cells in various sites and under different conditions of infection and inflammation that engage in these dichotomous activities of tissue clearance vs. initiation of anti-pathogen effector responses, (2) identifying the receptors and signaling mechanisms that underlie these different functionalities, and (3) defining the integrated function of these cells through cross-regulatory connections. When placed in the larger context of additional mechanisms that enforce immune homeostasis, such as regulatory T cells, feedback expression of inhibitory receptors, central and peripheral deletional mechanisms, and the like, the results of these investigations will help identify components of the regulatory apparatus whose malfunction can give rise to autoimmune disease and suggest targets for future therapeutic efforts.