The role of cross-presentation of self-antigens by dendritic cells in type 1 diabetes

树突状细胞交叉呈递自身抗原在 1 型糖尿病中的作用

• 批准号: 9050254
• 负责人: Vivek Durai
• 金额: $ 2.97万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9050254
• 关键词: Affect; Alleles; American; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Backcrossings; Beta Cell; Biological Models; CD8B1 gene; Cell Surface Receptors; Cells; Cross Presentation; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Diabetes Mellitus; Exhibits; Family; Genetic; Histocompatibility Antigens Class I; Hyperglycemia; In Vitro; Inbred NOD Mice; Infiltration; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Knock-out; Knockout Mice; Lymphocyte; Measures; Mediating; Modeling; Monomeric GTP-Binding Proteins; Mouse Strains; Mus; Non obese; Pathogenesis; Pathway interactions; Phagosomes; Play; Predisposition; Process; Recruitment Activity; Resistance; Role; Structure of beta Cell of islet; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissues; Work; autoreactive T cell; cytotoxic; diabetic; extracellular; human disease; in vivo; islet; member; mouse model; novel; pathogen; prevent; public health relevance; receptor; response; therapeutic development; trafficking

 DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an autoimmune disease that affects more than 3 million Americans. It is characterized by the infiltration and destruction of beta cells in the pancreatic islets of Langerhans by CD4+ and CD8+ T cells. Recent work from our labs has also demonstrated that CD8α+ dendritic cells are essential for the initiation of T1D. These cells are normally responsible for cross-presentation of extracellular antigens in order to activate a cytotoxic T cell response against intracellular pathogens. CD8α+ dendritic cells may, however, also inappropriately cross-present self-antigens, such as from pancreatic beta cells, in order to initiate a CD8+ T cell response against normal host tissues. This inadvertent function may explain why they are necessary for the initiation of T1D. Determining the mechanisms of cross-presentation and its role in autoimmunity may therefore provide vital clues into the pathogenesis of T1D, and may also hasten the development of therapeutic measures to prevent its onset. In this proposal, we will identify the mechanisms by which cross-presentation occurs and the role it plays in T1D. In order to investigate these questions, we have generated novel Rab43 knockout mice. CD8α+ dendritic cells from these mice exhibit deficient in vitro and in vivo cross-presentation. In Aim 1, we will identify the intracellular vesicular pathways to which Rab43 directs antigen for cross-presentation. We will also determine what extracellular receptors recruit Rab43 to phagosomes in order to cross-present their contents. In Aim 2, we will determine whether deficient cross-presentation impacts the development of T1D. We will use the non-obese diabetic (NOD) mouse strain as a model of T1D, as it recapitulates many features of the human disease including the spontaneous destruction of islet beta cells. We will backcross the Rab43 knockout allele onto the NOD background in order to produce the NOD.Rab43-/- strain, which will exhibit deficient cross- presentation on a background of susceptibility to diabetes. We will characterize whether these mice are resistant to the development of hyperglycemia and the destruction of islet beta cells. We will further analyze whether this strain has a selective deficiency in activating the autoreactive CD8+ T cells that mediate the destruction of beta cells. Together, the findings generated from this proposal should determine whether cross- presentation plays a role in the pathogenesis of T1D, and, if so, will also identify the pathways whose therapeutic modulation could prevent the initiation of the autoimmune response.

 描述（由申请人提供）：1型糖尿病（T1 D）是一种自身免疫性疾病，影响超过300万美国人。其特征在于胰岛中的β细胞被CD 4+和CD 8 + T细胞浸润和破坏。我们实验室最近的工作也表明，CD 8 α+树突状细胞对T1 D的启动至关重要。 这些细胞通常负责细胞外抗原的交叉呈递，以激活针对细胞内病原体的细胞毒性T细胞应答。然而，CD 8 α+树突状细胞也可能不适当地交叉呈递自身抗原，例如来自胰腺β细胞的抗原，以启动针对正常宿主组织的CD 8 + T细胞应答。这种无意的功能可以解释为什么它们对于T1 D的启动是必要的。因此，确定交叉呈递的机制及其在自身免疫中的作用可能为T1 D的发病机制提供重要线索，也可能加速预防其发作的治疗措施的发展。 在本提案中，我们将确定交叉呈递发生的机制及其在T1 D中所起的作用。为了研究这些问题，我们已经产生了新的Rab 43基因敲除小鼠。来自这些小鼠的CD 8 α+树突状细胞表现出体外和体内交叉呈递缺陷。在目标1中，我们将确定Rab 43指导抗原交叉呈递的细胞内囊泡途径。我们还将确定哪些细胞外受体将Rab 43招募到吞噬体中以交叉呈递其内容物。在目标2中，我们将确定交叉呈递缺陷是否会影响T1 D的发展。我们将使用非肥胖糖尿病（NOD）小鼠品系作为T1 D模型，因为它概括了人类疾病的许多特征，包括胰岛β细胞的自发破坏。我们将Rab 43敲除等位基因回交到NOD背景上，以产生NOD.Rab43-/-菌株，其将在糖尿病易感性背景下表现出交叉呈递缺陷。我们将描述这些小鼠是否对高血糖症的发展和胰岛β细胞的破坏具有抵抗力。我们将进一步分析这种菌株是否在激活介导β细胞破坏的自身反应性CD 8 + T细胞方面存在选择性缺陷。总之，从该提议产生的发现应确定交叉呈递是否在T1 D的发病机制中起作用，并且如果是这样，还将鉴定其治疗调节可以防止自身免疫应答启动的途径。