Regulation of dendritic cell inflammatory responses

描述（由申请人提供）：树突状细胞（DC）存在于先天免疫和适应性免疫的交叉点，因此在宿主对感染的反应和维持自身耐受性中发挥复杂和关键的作用。DC通过多种受体识别病原体，这可以导致病原体内化和快速产生有助于炎症反应的细胞因子。这种病原体识别还导致细胞表面MHC分子和共刺激分子的上调，这使得DC能够成为向初始T细胞呈递病原体衍生肽的有效抗原呈递细胞。以这种方式，DC对于适应性免疫应答是必需的，但如果不通过自身抗原的炎性呈递进行适当调节，也可以促进自身免疫。DAP 12和FcR 3是两种DC表达的信号传导衔接子，其通过基于免疫受体酪氨酸的激活基序（ITAM）来进行信号传导。携带ITAM的信号传导适配器DAP 12和FcR 3以几种方式调节DC功能。在体外，DAP 12和FcR 3抑制Toll样受体（TLR）反应并调节凋亡细胞对DC功能的抗炎作用。在体内，DAP 12和FcR 3调节DC数量，并通过增加全身性IL-17促进嗜中性粒细胞。最重要的是，DAP 12和FcR 3调节自身耐受性的维持-DAP 12-/-FcR 3-/-小鼠发生狼疮样疾病，伴随抗核抗体、IG在肾小球中沉积和肾小球破坏。本提案的目的是确定DAP 12和FcR 3在体内和体外调节树突状细胞应答的机制，目的是确定这些受体如何帮助防止狼疮样自身免疫的发展。具体而言，我们将1）鉴定抑制常规和浆细胞样树突状细胞中TLR应答所需的FcR 3相关免疫受体; 2）测试树突状细胞中的DAP 12和FcR 3通过调节DC对凋亡细胞的应答来控制中性粒细胞稳态的假设;和3）确定在DCs中特异性缺乏DAP 12和FcR 3是否导致在DAP 12-/-FcR 3-/-小鼠中观察到的抗核抗体产生和狼疮样疾病。 我们已经证明，DAP 12和FcR 3调节树突状细胞功能的几个方面-TLR信号传导，对凋亡细胞的反应和自身耐受性的维持-所有这些都与小鼠和人类狼疮样自身免疫的发展有关。本提案的目的是确定DAP 12和FcR 3在体内和体外调节树突状细胞应答的机制，目的是确定这些受体如何帮助防止狼疮样自身免疫的发展。这些研究不仅有助于阐明树突状细胞在免疫应答过程中的功能是如何调节的，而且还有助于阐明树突状细胞活化在稳态下是如何调节的。这项工作将深入了解如何操纵免疫系统，以防止系统性自身免疫的发展。 公共卫生相关性：树突状细胞在启动炎症反应和免疫反应方面都很重要。这些研究将有助于阐明树突状细胞的功能是如何调节的存在和不存在感染。这项工作将深入了解如何操纵免疫系统，以实现更有效地消除病原体，并防止系统性自身免疫性疾病，如系统性红斑狼疮的发展。

DESCRIPTION (provided by applicant): Dendritic cells (DC) exist at the crossroads of innate and adaptive immunity and therefore play a complex and critical role in the host response to infection and in maintenance of self-tolerance. DCs recognize pathogens through a variety of receptors, and this can result in pathogen internalization and rapid production of cytokines that contribute to the inflammatory response. This pathogen recognition also leads to the upregulation of cell surface MHC molecules and costimulatory molecules, which enables DCs to become potent antigen presenting cells presenting pathogen-derived peptides to naive T cells. In this way, DCs are essential for the adaptive immune response, but can also promote autoimmunity if not properly regulated through the inflammatory presentation of self-antigens. DAP12 and FcR3 are two DC-expressed signaling adapters that signal through immunoreceptor tyrosine-based activation motifs (ITAMs). The ITAM-bearing signaling adapters DAP12 and FcR3 regulate DC function in several ways. In vitro, DAP12 and FcR3 inhibit Toll-like receptor (TLR) responses and regulate the anti-inflammatory effects of apoptotic cells on DC function. In vivo, DAP12 and FcR3 regulate DC numbers and contribute to neutrophilia through increased systemic IL-17. Most importantly, DAP12 and FcR3 regulate the maintenance of self-tolerance-DAP12-/-FcR3-/- mice develop lupus-like disease with anti-nuclear antibodies, Ig deposition in the kidney glomeruli and glomerular destruction. The aims of this proposal seek to define the mechanisms by which DAP12 and FcR3 regulate dendritic cell responses in vivo and in vitro with the goal of identifying how these receptors help protect from the development of lupus-like autoimmunity. Specifically, we will 1) identify the FcR3-associated immunoreceptors required for inhibition of TLR responses in conventional and plasmacytoid dendritic cells; 2) test the hypothesis that DAP12 and FcR3 in dendritic cells control neutrophil homeostasis by regulating DC responses to apoptotic cells; and 3) determine if lack of DAP12 and FcR3 specifically in DCs causes the anti-nuclear antibody production and lupus-like disease seen in DAP12-/-FcR3-/- mice. We have shown that DAP12 and FcR3 regulate several aspects of dendritic cell function-TLR signaling, responses to apoptotic cells, and maintenance of self-tolerance-all of which have been associated with the development of lupus-like autoimmunity in mice and humans. The aims of this proposal seek to define the mechanisms by which DAP12 and FcR3 regulate dendritic cell responses in vivo and in vitro with the goal of identifying how these receptors help protect from the development of lupus-like autoimmunity. These studies will not only help elucidate how dendritic cell function is regulated during immune responses, but also how dendritic cell activation is regulated in the steady state. This work will give insights into how to manipulate the immune system to prevent the development of systemic autoimmunity. PUBLIC HEALTH RELEVANCE: Dendritic cells are important in initiating both inflammatory responses and immune responses. These studies will help elucidate how dendritic cell function is regulated both in the absence and presence of infection. This work will give insights into how to manipulate the immune system to achieve more efficient elimination of pathogens and to prevent the development of systemic autoimmune disease, such as systemic lupus erythematosus.