Regulation of dendritic cell inflammatory responses

描述(申请人提供)：树突状细胞(DC)存在于天然免疫和获得性免疫的十字路口，因此在宿主对感染的反应和维持自身耐受性方面发挥着复杂和关键的作用。DC通过多种受体识别病原体，这可以导致病原体内化并迅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，使DC成为强大的抗原提呈细胞，将病原体衍生的多肽递送给幼稚的T细胞。在这种情况下，DC对于适应性免疫反应是必不可少的，但如果没有通过自身抗原的炎性递呈进行适当的调节，它也可以促进自身免疫。DAP12和FcR3是两个DC表达的信号适配器，通过基于免疫受体酪氨酸的激活基序(ITAM)进行信号传递。携带ITAM的信号适配器DAP12和FcR3以多种方式调节DC功能。在体外，DAP12和FcR3抑制Toll样受体(TLR)的反应，调节凋亡细胞对DC功能的抗炎作用。在体内，DAP12和FcR3通过增加全身IL-17调节DC数量并促进中性粒细胞增多。最重要的是，DAP12和FcR3调节自身耐受性的维持-DAP12-/-FcR3-/-小鼠发生狼疮样疾病，出现抗核抗体，Ig沉积在肾小球和肾小球破坏。这项建议的目的是确定DAP12和FcR3在体内和体外调节树突状细胞反应的机制，目的是确定这些受体如何帮助保护狼疮样自身免疫的发展。具体地说，我们将1)确定在常规和浆细胞样树突状细胞中抑制TLR反应所需的FcR3相关免疫受体；2)检验树突状细胞中的DAP12和FcR3通过调节DC对凋亡细胞的反应来控制中性粒细胞动态平衡的假设；以及3)确定DC中缺乏DAP12和FcR3是否导致DAP12-/-FcR3-/-小鼠中产生抗核抗体和狼疮样疾病。我们已经证明，DAP12和FcR3调节树突状细胞功能的几个方面-TLR信号，对凋亡细胞的反应，以及自我耐受的维持-所有这些都与狼疮样自身免疫在小鼠和人类的发展有关。这项建议的目的是确定DAP12和FcR3在体内和体外调节树突状细胞反应的机制，目的是确定这些受体如何帮助保护狼疮样自身免疫的发展。这些研究不仅将有助于阐明树突状细胞在免疫反应中的功能是如何调节的，也将有助于阐明树突状细胞的激活在稳定状态下是如何被调节的。这项工作将为如何操纵免疫系统以防止系统性自身免疫的发展提供见解。 公共卫生相关性：树突状细胞在启动炎症反应和免疫反应中都很重要。这些研究将有助于阐明在没有感染和存在感染的情况下，树突状细胞的功能是如何调节的。这项工作将为如何操纵免疫系统以实现更有效地消除病原体和防止系统性自身免疫性疾病的发展提供见解，如系统性红斑狼疮。

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.