TIM-1, TIM-3 and TIM-4: A gene family that regulates tolerance and immunity

TIM-1、TIM-3 和 TIM-4：调节耐受性和免疫性的基因家族

• 批准号: 8831793
• 负责人: Rosemarie H DeKruyff
• 金额: $ 7.69万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8831793
• 关键词: TIM; gene; family; regulates; tolerance

PROJECT SUMMARY (See instructions): The TIM gene family was identified using a congenic mouse model in which polymorphisms in TIM-1 and TIM-3 wre associated with Th1-Th2 differentiation and allergen-induced ainway hyperreactivity (AHR) between BALB/c and congenic HBA mice. The long-term goals of Project 3 are to understand how the Tim genes regulate peripheral tolerance, adaptive immune responses, and allergy. In the previous grant period we showed that TIM-1 is an important costimulatory molecule for T cells, that TIM-1 and TIM-4 modulate T cell responses and the development of tolerance, and that TIM-1 and TIM-4 are receptors for phosphatidylserine (PtdSer), a key molecule for recognition and uptake of apoptotic cells. We have found that TIM-3, expressed on Th1 cells and APC, is also a receptor for PtdSer and that the allelic variants of TIM-3 associated with asthma differ in their recognition of PtdSer. These results together suggest a new paradigm for TIM proteins as PtdSer receptors that by regulating the recognition and clearance of apoptotic cells, can regulate tissue homeostasis, T cell responses and the induction of peripheral tolerance. In Specific Aim 1 we will determine the mechanisms by which TIM-4 expressed on APC, and TIM-1, expressed on activated T cells and Th2 cells, regulate oral tolerance and prevent food allergy. We will examine mechanisms by which TIM-4 blockade inhibits oral tolerance induction. In Specific Aim 2, we will characterize the cell types and APC subset(s) in the lamina propria and mesenteric lymph node that express TIM-4, the conditions that modulate expression of TIM-3 and TIM-4 following exposure to danger signals such as bacterial products that initiate food allergy. We will examine the consequences of T cell interaction with TIM-expressing APC on T cell subset differentiation. In Specific Aim 3 we will investigate the role of TIM-3 polymorphic variants, which we have recently shown differ in recognition of apoptotic cells, in modulation of immune responses in BALB/c and HBA mice, and determine the roles of TIM-1 and TIM-3 in modulating the development of airway hyperreactivity in these strains. We have developed unique reagents that will enable us to accomplish these goals. We have generated panels of anti-TIM-1 and TIM-4 mAbs, we have generated TIM-4 and TIM-1 transgenic mice, and TlM-1 deficient mice are now breeding in our colony. Our laboratory has extensive experience in the study of tolerance as a mechanism that protects against Th2-driven immune responses and in the study of dendritic cells (DCs) and antigen-specific CD4+ Tpeg cells. These studies will greatly improve our understanding of immune regulation and lead to new therapies for inflammatory diseases.

项目摘要（参见说明）： TIM 基因家族是使用同源小鼠模型进行鉴定的，其中 TIM-1 的多态性 TIM-3 与 BALB/c 和同系 HBA 小鼠之间的 Th1-Th2 分化和过敏原诱导的 AHR 相关。项目 3 的长期目标是了解 Tim 基因如何调节外周耐受、适应性免疫反应和过敏。在之前的资助期间，我们表明TIM-1是T细胞的重要共刺激分子，TIM-1和TIM-4调节T细胞反应和耐受性的发展，并且TIM-1和TIM-4是磷脂酰丝氨酸（PtdSer）的受体，PtdSer是识别和摄取凋亡细胞的关键分子。我们发现，在 Th1 细胞和 APC 上表达的 TIM-3 也是 PtdSer 的受体，并且与哮喘相关的 TIM-3 等位基因变体在识别 PtdSer 方面有所不同。这些结果共同提出了 TIM 蛋白作为 PtdSer 受体的新范例，通过调节凋亡细胞的识别和清除，可以调节组织稳态、T 细胞反应和诱导外周耐受。 在具体目标 1 中，我们将确定 TIM-4 在 APC 和 TIM-1 上表达的机制， 在活化的 T 细胞和 Th2 细胞上表达，调节口服耐受性并预防食物过敏。我们将 检查 TIM-4 阻断抑制口服耐受诱导的机制。在具体目标 2 中，我们将描述表达 TIM-4 的固有层和肠系膜淋巴结中的细胞类型和 APC 子集，这是在暴露于危险信号（例如引发食物过敏的细菌产物）后调节 TIM-3 和 TIM-4 表达的条件。我们将研究 T 细胞与表达 TIM 的 APC 相互作用对 T 细胞亚群分化的影响。在具体目标 3 中，我们将研究 TIM-3 多态性变体的作用，我们最近发现 TIM-3 多态性变体在识别凋亡细胞、调节 BALB/c 和 HBA 小鼠的免疫反应方面有所不同，并确定 TIM-1 和 TIM-3 在调节这些菌株气道高反应性发展中的作用。 我们开发了独特的试剂，使我们能够实现这些目标。我们有 产生了抗 TIM-1 和 TIM-4 mAb 组，我们已经产生了 TIM-4 和 TIM-1 转基因小鼠，并且 TIM-1 缺陷小鼠现在正在我们的群体中繁殖。我们的实验室在耐受性研究（作为一种防止 Th2 驱动的免疫反应的机制）以及树突状细胞 (DC) 和抗原特异性 CD4+ Tpeg 细胞的研究方面拥有丰富的经验。这些研究将极大地提高我们对免疫调节的理解，并带来炎症性疾病的新疗法。