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

基本信息

批准号：
7995554
负责人：
Rosemarie H DeKruyff
金额：
$ 20.59万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7995554
关键词：
Affect Allergens Antigens Apoptotic Asthma Atopic Dermatitis Breeding Cell Communication Cells Congenic Mice Dendritic Cells Development Disease Disease susceptibility Exposure to Food Food Hypersensitivity Gene Family General Population Generations Genes Genetic Polymorphism Genetic Variation Goals Grant Gut associated lymphoid tissue Homeostasis Hypersensitivity Immune Immune response Immunity Inbred BALB C Mice Inflammatory Instruction Laboratories Lamina Propria Lead Link Mediating Mesentery Molecular Mus Pathway interactions Phosphatidylserines Play Proteins Public Health Reagent Regulation Regulatory T-Lymphocyte Relative (related person)Rheumatoid Arthritis Role Signal Transduction Susceptibility Gene T cell response T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Th1 Cells Th1/Th2 Differentiation Pathway Th2 Cells Tissues Transgenic Mice Variant airway hyperresponsiveness allergic response atopy cell type congenic experience improved in vivo lymph nodes mouse model novel oral tolerance peripheral tolerance phosphatidylserine receptor prevent receptor response uptake

项目摘要

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。