Dissecting Dendritic Cell Function in Autoimmune Diabetes

剖析自身免疫性糖尿病中树突状细胞的功能

• 批准号: 8308662
• 负责人: JONATHAN David KATZ
• 金额: $ 32.62万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308662
• 关键词: Ablation; Adoptive Transfer; Affect; Antigen-Presenting Cells; Antigens; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Back; CD4 Positive T Lymphocytes; Cell Communication; Cell physiology; Cells; Child; Child health care; Childhood; Coculture Techniques; Data; Dendritic Cells; Diabetes Mellitus; Diphtheria Toxin; Disease; Environment; ITGAM gene; ITGAX gene; In Situ; In Vitro; Inbred NOD Mice; Inflammation; Insulin-Dependent Diabetes Mellitus; Interferons; Islets of Langerhans; Lead; Link; Mediating; Modeling; Modification; Molecular; Myelogenous; Non obese; Pancreas; Pathogenesis; Pathology; Peripheral; Play; Production; Proliferation Marker; Publishing; Regulation; Role; Severities; Signal Transduction; Site; Structure of beta Cell of islet; T cell regulation; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Tryptophan 2,3 Dioxygenase; United States; Work; conditioning; cytokine; design; diabetic; disorder control; immunoregulation; improved; in vivo; inhibitor/antagonist; islet; killer T cell; lymph nodes; mouse model; research study

DESCRIPTION (provided by applicant): The autoimmune pathogenesis of Type 1 diabetes (T1D), the leading childhood autoimmune disease, is experimentally-modeled in the non-obese diabetic (NOD) mouse. NOD mouse studies have revealed that the so-called, diabetogenic, or disease-causing, T cells are central to the pathogenesis of T1D; yet, why these T cells are not effectively controlled via either central or peripheral mechanisms of tolerance is not fully understood. It is clear, however, that these T cells receive critical pro- and anti-proliferative signals from antigen presenting cells (APC) such as dendritic cells (DC), and that these T cell-APC interactions dramatically influence the effector T cell response to pancreatic beta cell antigens and the subsequent course of disease. Yet the molecular mechanisms underlying the control of diabetogenic T cells remain unsolved. Using a diphtheria toxin-mediated ablation model, we found that the myeloid dendritic cells (mDC) subset acts to promote T1D by priming diabetogenic T cells to pancreatic beta cell antigens in vivo. Conversely, depleting plasmacytoid DC (pDC) exacerbates the pathology- increasing both the number and severity of infiltrated islets, suggesting that, once activated, diabetogenic T cells are still under regulatory control by the pDC subset in vivo. Importantly, preliminary studies suggest a direct molecular mechanism, as the presence of intra-islet pDC correlated not only with reduced pathology but also with the localized expression of indoleamine 2,3-dioxygenase (IDO), a potent inhibitor of T cell proliferation. IDO is elicited from pDC by both type 1 and type 2 interferons (IFN). Natural Killer T (NKT) cells regulate diabetogenic CD4+ T cells in an IFN-9-dependent fashion. Using an adoptive transfer model, we found that CD4+ NKT cells are capable of regulating CD4+ diabetogenic effector T cells in vivo. This NKT cell-mediated immunoregulation occurs in the pancreas and pancreatic lymph nodes (PLN) and requires NKT cells to produce IFN-9. The apparent target of IFN-9 is host DC and not the diabetogenic T cells themselves, suggesting that the action of the NKT cells is indirect via conditioning of the host DC compartment. The most likely DC target is the pDC subset; and the most likely molecular effector is the induction of IDO. Preliminary studies suggest a causal link between NKT cells and pDC in the regulation of diabetogenic CD4+ T cells in the NOD mouse. Taken together, these findings have led us to hypothesize: (i) that NKT cells and pDC work in concert to regulate diabetogenic CD4+ T cells and modulate the tempo of insulitis in vivo; (ii) that pancreatic pDC can directly activate NKT cells to produce IFN-9; and (iii) that this IFN-9 induces pDC to in turn make IDO, which results in a localized environment that limits diabetogenic T cell proliferation. To test our hypotheses we propose the following two specific aims: Aim 1: To determine if pDC from the pancreas and PLN of NOD mice directly or indirectly activate NKT cells in vitro and in vivo. Aim 2: To determine if NKT cell-produced INF-9 and pDC-produced IDO establish a regulatory circuit that controls diabetogenic T cells in vivo.

描述（由申请人提供）：领先的儿童自身免疫性疾病的1型糖尿病（T1D）的自身免疫发病机理在非肥胖糖尿病（NOD）小鼠中进行了实验模型。 NOD小鼠的研究表明，所谓的糖尿病生成或引起疾病的T细胞对于T1D发病机理至关重要。但是，为什么尚未完全了解这些T细胞通过中央或外围机制有效控制这些T细胞的原因。但是，很明显，这些T细胞从抗原呈递细胞（APC）（例如树突状细胞（DC））中接收关键的促和抗增殖信号，并且这些T细胞APC相互作用极大地影响了对胰腺β细胞抗原的效应T细胞反应，以及疾病的后续过程。然而，控制糖尿病性T细胞控制的基于的分子机制仍未解决。使用白喉毒素介导的消融模型，我们发现髓样树突状细胞（MDC）子集可通过将糖尿病性T细胞启动到体内胰腺β细胞抗原来促进T1D。相反，耗尽的浆细胞类动物DC（PDC）加剧了病理学 - 增加了浸润胰岛的数量和严重程度，这表明一旦激活，糖尿病性T细胞仍会受到PDC子集的调节性控制。重要的是，初步研究提出了一种直接的分子机制，因为ISLET内PDC的存在不仅与减少的病理学相关，还与吲哚胺2,3-二氧酶（IDO）的局部表达相关，这是T细胞增殖的有效抑制剂。 IDO是由1型和2型干扰素（IFN）从PDC中引起的。天然杀伤T（NKT）细胞以IFN-9依赖性方式调节糖尿病性CD4+ T细胞。使用收养转移模型，我们发现CD4+ NKT细胞能够在体内调节CD4+糖尿病效应T细胞。该NKT细胞介导的免疫调节发生在胰腺和胰腺淋巴结（PLN）中，并需要NKT细胞产生IFN-9。 IFN-9的明显靶标是宿主DC，而不是糖尿病性T细胞本身，这表明NKT细胞的作用是通过宿主DC室的条件间接的。最有可能的直流目标是PDC子集。最可能的分子效应器是诱导IDO。初步研究表明，NKT细胞与PDC之间在NOD小鼠中调节糖尿病性CD4+ T细胞中的因果关系。综上所述，这些发现使我们假设：（i）NKT细胞和PDC协同起作用，以调节糖尿病性CD4+ T细胞并调节体内胰岛炎的速度； （ii）胰腺PDC可以直接激活NKT细胞以产生IFN-9； （iii）这种IFN-9诱导PDC又导致IDO，这导致局部环境限制了糖尿病性T细胞增殖。为了检验我们的假设，我们提出了以下两个特定目的：目标1：确定来自NOD小鼠的胰腺和PLN的PDC是否直接或间接地在体外和体内激活NKT细胞。 AIM 2：确定NKT细胞生产的INF-9和PDC生产的IDO是否建立了控制体内糖尿病性T细胞的调节回路。