Impact of insulin receptor signaling on T cell function and adaptive immunity

2型糖尿病（T2DM）是西方社会的严重问题。虽然血管病变是大多数并发症的原因，但T2DM患者免疫系统受损也会引起问题。活化的T细胞表达胰岛素受体（INSR）和下游信号分子，这可能是足够的免疫应答所必需的。为了研究INSR对T细胞功能的作用，我们将使用可诱导的敲低大鼠，允许其在多西环素给药后失活。首先，我们将确定在缺乏INSR的情况下，辅助性T细胞、细胞毒性T细胞和调节性T细胞的功能是否受损。在第二部分中，我们将研究T细胞中INSR所采用的信号通路，并挑战我们的假设，即它可能与CD28协同增强葡萄糖动员。抗原特异性T细胞将在两个模型中进行分析，涉及它们的迁移行为，这是效应细胞特别需要能量的特征。 最后，我们将产生造血干细胞嵌合体，其中基因失活仅限于免疫系统，以研究INSR表达对两种不同炎症性疾病的影响。为此，我们将诱导实验性自身免疫性脑脊髓炎（EAE）作为细胞免疫的典型模型，过敏性气道超敏反应（AAH）作为体液免疫反应的一个例子。总的来说，这些分析应提供深入了解INSR信号在免疫系统中的作用和机制，并有助于更好地了解T2DM患者的免疫状态受损。

Type 2 diabetes mellitus (T2DM) is a severe problem of western societies. While angiopathies account for most complications, problems are also caused by the compromised immune system of T2DM patients. Activated T cells express insulin receptors (INSR) and downstream signaling molecules, which is presumably required for an adequate immune response. To investigate the role of the INSR for T cell function we will use inducible knock-down rats allowing for its inactivation after Doxycycline administration. Initially, we will determine whether the function of T helper, cytotoxic T and regulatory T cells is compromised in the absence of the INSR. In the second part, we will investigate the signaling pathways employed by the INSR in T cells and challenge our hypothesis that it may serve to enhance glucose mobilization in concert with CD28. Antigen-specific T cells will be analyzed in two models concerning their migratory behavior, which is a particularly energy-demanding feature of effector cells. Finally, we will generate hematopoietic stem cell chimeras where gene inactivation is limited to the immune system to study the impact of INSR expression on two distinct inflammatory diseases. To this end, we will induce experimental autoimmune encephalomyelitis (EAE) as a typical model for cellular immunity, and allergic airway hypersensitivity (AAH) as an example of a humoral immune response. Collectively, these analyses should provide insight into the role and mechanism of INSR signaling in the immune system and help to better understand the compromised immune status of T2DM patients.