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: 8119440
• 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/8119440
• 关键词: Ablation; Adoptive Transfer; Antigen-Presenting Cells; Antigens; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; CD4 Positive T Lymphocytes; Cell Communication; Cell physiology; Childhood; Dendritic Cells; Diphtheria Toxin; Disease; Environment; In Vitro; Inbred NOD Mice; Insulin-Dependent Diabetes Mellitus; Interferons; Link; Mediating; Modeling; Molecular; Myelogenous; Pancreas; Pathogenesis; Pathology; Peripheral; Regulation; Severities; Signal Transduction; Structure of beta Cell of islet; T cell response; T-Cell Proliferation; T-Lymphocyte; Testing; Tryptophan 2,3 Dioxygenase; Work; conditioning; immunoregulation; in vivo; inhibitor/antagonist; islet; killer T cell; lymph nodes

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）的自身免疫发病机制是主要的儿童自身免疫性疾病，在非肥胖糖尿病（NOD）小鼠中进行了实验建模。NOD小鼠研究表明，所谓的致糖尿病或致病的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有效地控制，这一点尚不完全清楚。然而，很明显，这些T细胞接收来自抗原呈递细胞（APC）如树突状细胞（DC）的关键促增殖和抗增殖信号，并且这些T细胞-APC相互作用显著影响效应T细胞对胰腺β细胞抗原的反应和随后的疾病进程。然而，控制致糖尿病T细胞的分子机制仍未得到解决。利用白喉毒素介导的消融模型，我们发现髓样树突状细胞（mDC）亚群通过在体内将糖尿病源性T细胞导入胰腺β细胞抗原来促进T1D。相反，消耗浆细胞样DC （pDC）加剧了病理-增加浸润胰岛的数量和严重程度，这表明，一旦激活，糖尿病源性T细胞在体内仍受pDC亚群的调节控制。重要的是，初步研究表明了直接的分子机制，因为胰岛内pDC的存在不仅与病理减少有关，而且与吲哚胺2,3-双加氧酶（IDO）的局部表达有关，IDO是一种有效的T细胞增殖抑制剂。IDO可由1型和2型干扰素（IFN）诱导。自然杀伤T细胞（NKT）以ifn -9依赖性的方式调节糖尿病性CD4+ T细胞。通过过继转移模型，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，而不是致糖尿病性T细胞本身，这表明NKT细胞的作用是通过调节宿主DC隔室间接进行的。最可能的直流目标是pDC子集；最可能的分子效应是诱导IDO。初步研究表明，NKT细胞和pDC在NOD小鼠中调节致糖尿病CD4+ T细胞之间存在因果关系。综上所述，这些发现使我们假设：(i) NKT细胞和pDC协同调节糖尿病性CD4+ T细胞并调节体内胰岛素的速度；（ii）胰腺pDC可直接激活NKT细胞产生IFN-9；（iii） IFN-9诱导pDC反过来产生IDO，从而形成限制糖尿病性T细胞增殖的局部环境。为了验证我们的假设，我们提出了以下两个具体目标：目的1：确定NOD小鼠胰腺和PLN中的pDC是否直接或间接激活NKT细胞。目的2：确定NKT细胞产生的INF-9和pdc产生的IDO是否在体内建立了控制糖尿病性T细胞的调节回路。