Regulation of IDDM by NKT cells

NKT 细胞对 IDDM 的调节

• 批准号: 6623203
• 负责人: ALBERT S. BENDELAC
• 金额: $ 21.62万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623203
• 关键词: CD1 molecule; NOD mouse; T cell receptor; autoimmunity; cell differentiation; cell migration; cellular pathology; diabetes mellitus genetics; disease /disorder proneness /risk; family genetics; genetically modified animals; human subject; insulin dependent diabetes mellitus; interleukin 15; natural killer cells; patient oriented research; tissue mosaicism

The autoimmune destruction of insulin producing cells in IDDM is critically controlled by the conserved CD1d-autoreactive NKT cells. NKT cells express an invariant TCR alpha chain combined with a restricted set of TCR Vbeta families (Valpha14- Jalpha18/Vbeta8 in mouse and Valpha24-Jalpha18/Vbeta11 in humans) as well as a panoply of receptors of the NK lineage. Upon in vivo stimulation, they promptly release TH2 cytokines that suppress diabetes. We have developed a set of tools, such as CD1d/alphaGalCer tetramers specifically staining the semi- invariant NKT cell TCR, which allow us for the first time to specifically study NKT cells in vivo in both mice and humans. This application proposes to dissect and compare the mechanisms underlying the NKT cell defects associated with IDDM in mice and humans. The specific aims are Specific Aim number 1: To identify the defective stages and mechanisms of Valpha14 NKT cell development in NOD mice. We will dissect the defect in NKT cell thymic and post-thymic development, and identify the defective cellular and molecular mechanisms underlying the NOD phenotype. In particular, the nature of the defective cell-type will be dissected using a mixed chimera system in vivo, and the role of IL-15, a key cytokine in NKT cell development, will be investigated in vitro and in vivo. Specific Aim number 2: To determine the contribution of CD1d and Valpha14 T cells to NOD mouse diabetes. We will study NOD.CD1d0 mice and their complementation cross with NOD.CD1d-Tg mice, as well as NOD.Jalpha180 mice, in order to test the hypothesis that NKT cells naturally regulate spontaneous diabetes. We will perform transfers of Valpha14 NKT cells in various combinations of mutant donor (e.g. IL-40) and host (e.g. CDld0) mice to dissect the functional basis of the protective effect. Specific Aim number 3: To identify the defective stages of Valpha24 NKT cell development in IDDM patients and their at risk relatives. We will define the human correlates of the mouse NKT cell subsets and dissect their defects in diabetic patients and at risk relatives. We will determine the timing and context of the NKT cell failure with respect to other established immunological markers of the disease process. These combined studies of mouse and human NKT cells have the potential to lead to novel strategies for the prediction and prevention of autoimmune diabetes in humans at risk for this disease.

IDDM中胰岛素产生细胞的自身免疫性破坏受保守的CD1D-AutoreActive NKT细胞的严格控制。 NKT细胞表达了一个不变的TCRα链，并结合了一组受限的TCR VBETA家族（valpha14- jalpha18/vbeta8，在人类中和valpha24-jalpha18/vbeta11中）以及NK LineAge受体的综合体。 在体内刺激后，它们迅速释放抑制糖尿病的Th2细胞因子。 我们已经开发了一组工具，例如专门染色半不变的NKT细胞TCR的CD1D/字母四聚体，这使我们首次可以在小鼠和人类中专门研究体内的NKT细胞。该应用建议剖析和比较小鼠和人类与IDDM相关的NKT细胞缺陷的机制。 具体目的是特定的目标数1：确定NOD小鼠中valpha14 NKT细胞发育的缺陷阶段和机制。 我们将剖析NKT细胞胸腺和胸膜后发育中的缺陷，并确定NOD表型的细胞和分子机制缺陷。 特别是，将使用混合嵌合体系统在体内解剖缺陷细胞类型的性质，并且将在体外和体内研究IL-15（关键细胞因子）在NKT细胞发育中的作用。具体目标2：确定CD1D和Valpha14 T细胞对点头小鼠糖尿病的贡献。 我们将研究NOD.CD1D0小鼠及其与NOD.CD1D-TG小鼠的互补交叉以及NOD.Jalpha180小鼠，以检验NKT细胞自然调节自发糖尿病的假设。 我们将在突变体供体（例如IL-40）和宿主（例如CDLD0）小鼠的各种组合中进行valpha14 NKT细胞的转移，以剖析保护效果的功能基础。特定目标3：确定IDDM患者及其处于风险亲戚的Valpha24 NKT细胞发育的有缺陷阶段。 我们将定义小鼠NKT细胞亚群的人类相关性，并在糖尿病患者和处于风险亲戚中剖析其缺陷。 我们将根据疾病过程的其他已建立的免疫学标记来确定NKT细胞衰竭的时间和背景。这些对小鼠和人类NKT细胞的合并研究有可能导致预测和预防这种疾病风险的人类自身免疫性糖尿病的新策略。