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（请参阅说明）： 使用先天小鼠模型鉴定了蒂姆基因家族，其中tim-1中的多态性 与Th1-Th2分化和过敏原诱导的AINWAY高反应性（AHR）相关的TIM-3 WRE在BALB/C和Encanic HBA小鼠之间。项目3的长期目标是了解TIM基因如何调节外围耐受性，适应性免疫反应和过敏。在上一个赠款期间，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，而Tim-1和Tim-4是用于磷脂酰丝氨酸（PTDSER），这是一种识别和吸收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的等位基因变体在其对PTDSER的识别方面有所不同。这些结果共同提出了TIM蛋白作为PTDSER受体的新范式，通过调节凋亡细胞的识别和清除，可以调节组织稳态，T细胞反应和周围耐受性的诱导。 在特定目标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，调节口服耐受性并防止食物过敏。我们将 检查TIM-4阻断抑制口服耐受诱导的机制。在特定的目标2中，我们将表征lamina propria和肠系膜淋巴结中的细胞类型和APC子集，该节点表达tim-4的条件，暴露于此类危险信号后，调节TIM-3和TIM-4的表达的条件作为启动食物过敏的细菌产品。我们将研究T细胞与表达TIM的APC在T细胞子集分化的后果。在特定的目标3中，我们将研究TIM-3多态变体的作用，我们最近显示的在凋亡细胞的识别方面有所不同，在BALB/C和HBA小鼠中免疫反应的调节中TIM-3用于调节这些菌株中气道高反应性的发展。 我们开发了独特的试剂，使我们能够实现这些目标。我们有 产生的抗TIM-1和TIM-4 mAb的面板，我们产生了TIM-4和TIM-1转基因小鼠，而TLM-1缺陷小鼠现在正在我们的菌落中繁殖。我们的实验室在研究耐受性的研究方面具有丰富的经验，作为一种防止Th2驱动的免疫反应以及树突状细胞（DCS）和抗原特异性CD4+ TPEG细胞的机制。这些研究将大大提高我们对免疫调节的理解，并导致新的炎症性疾病疗法。