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

项目总结(见说明)： 利用TIM-1基因多态的同源小鼠模型鉴定了TIM基因家族 TIM-3与BALB/c和同源HBA小鼠Th1-Th2分化和变应原诱导的气道高反应性(AHR)有关。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，我们发现TIM-1是T细胞的重要共刺激分子，TIM-1和TIM-4调节T细胞的反应和耐受的发展，TIM-1和TIM-4是磷脂酰丝氨酸(PtdSer)的受体，磷脂酰丝氨酸是识别和摄取凋亡细胞的关键分子。我们发现，表达在Th1细胞和APC上的Tim-3也是PtdSer的受体，与哮喘相关的TIM-3的等位基因变体对PtdSer的识别有所不同。这些结果提示了一种新的TIM蛋白作为PtdSer受体的范例，通过调节对凋亡细胞的识别和清除，可以调节组织内稳态、T细胞反应和诱导外周耐受。 在特定的目标1中，我们将确定TIM-4在APC上表达的机制，以及TIM-1， 在活化的T细胞和Th2细胞上表达，调节口服耐受性，预防食物过敏。我们会 研究TIM-4阻断抑制口服耐受诱导的机制。在特定的目标2中，我们将描述固有层和肠系膜淋巴结中表达TIM-4的细胞类型和APC亚群(S)，即在暴露于危险信号(如引发食物过敏的细菌制品)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多态变体在BALB/c和HBA小鼠免疫反应调节中的作用，并确定TIM-1和TIM-3在调节这些菌株的气道高反应性中的作用。 我们已经开发出独特的试剂，使我们能够实现这些目标。我们有 产生了抗TIM-1和TIM-4单抗，我们已经产生了TIM-4和TIM-1转基因小鼠，TLM-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作为一种保护Th2驱动的免疫反应的机制的研究以及在树突状细胞(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，并导致炎症性疾病的新疗法。

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.