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: 8517102
• 负责人: JONATHAN David KATZ
• 金额: $ 31.47万
• 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/8517102
• 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）：1 型糖尿病（T1D）是主要的儿童自身免疫性疾病，其自身免疫发病机制是在非肥胖糖尿病（NOD）小鼠中进行实验建模的。 NOD 小鼠研究表明，所谓的糖尿病性或致病性 T 细胞是 T1D 发病机制的核心；然而，为什么这些 T 细胞不能通过中枢或外周耐受机制得到有效控制尚不完全清楚。然而，很明显，这些 T 细胞从树突状细胞 (DC) 等抗原呈递细胞 (APC) 接收关键的促增殖和抗增殖信号，并且这些 T 细胞-APC 相互作用极大地影响效应 T 细胞对胰腺β细胞抗原和随后的病程。然而，控制致糖尿病 T 细胞的分子机制仍未得到解决。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) 亚群通过在体内将致糖尿病 T 细胞启动至胰腺 β 细胞抗原来促进 T1D。相反，消耗浆细胞样 DC (pDC) 会加剧病理学，增加浸润胰岛的数量和严重程度，这表明，一旦激活，致糖尿病 T 细胞仍处于体内 pDC 亚群的调节控制之下。重要的是，初步研究表明存在直接的分子机制，因为胰岛内 pDC 的存在不仅与病理学的减轻相关，而且与 T 细胞增殖的有效抑制剂吲哚胺 2,3-双加氧酶 (IDO) 的局部表达相关。 IDO 由 1 型和 2 型干扰素 (IFN) 从 pDC 引发。自然杀伤 T (NKT) 细胞以 IFN-9 依赖性方式调节糖尿病性 CD4+ T 细胞。使用过继转移模型，我们发现 CD4+ NKT 细胞能够在体内调节 CD4+ 糖尿病效应 T 细胞。这种 NKT 细胞介导的免疫调节发生在胰腺和胰腺淋巴结 (PLN) 中，需要 NKT 细胞产生 IFN-9。 IFN-9 的明显靶标是宿主 DC，而不是致糖尿病 T 细胞本身，这表明 NKT 细胞的作用是通过调节宿主 DC 区室来间接发挥作用的。最可能的 DC 目标是 pDC 子集；最可能的分子效应是IDO的诱导。初步研究表明 NKT 细胞和 pDC 在调节 NOD 小鼠糖尿病性 CD4+ T 细胞中存在因果关系。综上所述，这些发现使我们做出假设：(i) NKT 细胞和 pDC 协同作用，调节致糖尿病的 CD4+ T 细胞并调节体内胰岛素炎的进展； (ii)胰腺pDC可以直接激活NKT细胞产生IFN-9； (iii) 这种 IFN-9 诱导 pDC 进而产生 IDO，从而形成限制致糖尿病 T 细胞增殖的局部环境。为了检验我们的假设，我们提出以下两个具体目标： 目标 1：确定来自 NOD 小鼠胰腺的 pDC 和 PLN 是否在体外和体内直接或间接激活 NKT 细胞。目标 2：确定 NKT 细胞产生的 INF-9 和 pDC 产生的 IDO 是否建立了控制体内致糖尿病 T 细胞的调节回路。