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)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)小鼠中进行实验建模。NOD小鼠研究表明，所谓的糖尿病或致病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，还不完全清楚。然而，很明显，这些T细胞从树突状细胞(DC)等抗原提呈细胞(APC)接收关键的促增殖和抗增殖信号，并且这些T细胞与APC的相互作用显著影响效应T细胞对胰岛β细胞抗原的反应和随后的病程。然而，控制糖尿病T细胞的分子机制仍未解决。利用白喉毒素介导的消融模型，我们发现在体内，髓系树突状细胞(MDC)亚群通过启动胰岛β细胞抗原来促进T1D。相反，耗尽浆细胞样树突状细胞(PDC)会加剧病理--增加浸润性胰岛的数量和严重程度，这表明，一旦被激活，体内的非生理性T细胞仍然受到PDC亚群的调控。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的存在不仅与病理减轻有关，而且与吲哚胺2，3-双加氧酶(IDO)的局部表达有关，吲哚胺2，3-双加氧酶(IDO)是一种有效的T细胞增殖抑制因子。IDO是由1型和2型干扰素(干扰素)共同诱导的。自然杀伤T细胞(Natural Killer T，NKT)以一种依赖于干扰素-9的方式调节致糖尿病的CD4+T细胞。采用过继转移模型，我们发现在体内，CD4+NKT细胞具有调节CD4+糖尿病效应T细胞的能力。这种NKT细胞介导的免疫调节发生在胰腺和胰腺淋巴结(PLN)，需要NKT细胞产生干扰素-9。干扰素-9的明显靶点是宿主DC，而不是促糖尿病T细胞本身，这表明NKT细胞的作用是通过对宿主DC隔室的调节而间接的。最有可能的DC靶点是PDC亚群；最有可能的分子效应器是IDO的诱导。初步研究表明，NKT细胞和PDC在NOD小鼠中调节致糖尿病的CD4+T细胞方面存在因果联系。综上所述，这些发现使我们提出假设：(I)NKT细胞和PDC协同工作，调节体内糖尿病原性CD4+T细胞，并调节胰岛炎症的节奏；(Ii)胰腺PDC可以直接激活NKT细胞产生干扰素-9；(Iii)这种干扰素-9诱导PDC转而产生IDO，从而导致局部环境限制糖尿病原性T细胞的增殖。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小鼠胰腺来源的PDC和PLN在体外和体内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致糖尿病T细胞的调节电路。