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

免疫系统使用多种先天和适应性（抗原特异性）效应模式来保护宿主免受病原体入侵。这些免疫防御是强有力的，可能对宿主组织造成实质性损害，需要分层和交织的一系列控制机制来限制感染期间和感染后的附带损害。这种控制的一个关键位点是在炎症组织损伤期间抗原呈递到适应性免疫系统细胞的水平上，此时免疫系统必须满足两个相互竞争的义务——通过微生物抗原的免疫原性呈递促进有效的抗病原体反应，并通过避免这种自身抗原的免疫原性呈递来限制抗自身反应。在申请人最近的工作中，证明了用于实现这一目标的主要机制涉及吞噬细胞亚群（骨髓细胞）的特化，例如炎性巨噬细胞优先获取和呈现病原体来源的物质，而非自身来源的物质，而另一群非免疫原性吞噬细胞则吸收和处理组织碎片。这些细胞类型特异性活动也通过脂质介质在细胞亚群之间进行协调，脂质介质限制免疫原性炎性吞噬细胞亚群对自身成分的摄取。在本提案中，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)更彻底地定义不同骨髓细胞在不同部位和不同感染和炎症条件下的亚群特异性作用，这些作用参与组织清除与抗病原体效应反应的两种不同活动，(2)确定这些不同功能基础的受体和信号传导机制。(3)通过交叉调节连接确定这些细胞的综合功能。当在更大的背景下，加强免疫稳态的其他机制，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确定调节装置的组成部分，其功能障碍可能导致自身免疫性疾病，并为未来的治疗工作提出目标。

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.