TIM recognition of PtdSer on apoptotic cells and the regulation of immunity

TIM对凋亡细胞PtdSer的识别及免疫调节

基本信息

批准号：
8495892
负责人：
Rosemarie H DeKruyff
金额：
$ 40.18万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8495892
关键词：
Affect Alleles Allergens Anti-Inflammatory Agents Anti-inflammatory Antigens Apoptotic Asthma Atopic Dermatitis Autoimmune Diseases Binding CD80 gene Cells Congenic Mice Development Disease susceptibility Gene Family Genes Genetic Polymorphism Genetic Variation Goals Homeostasis Hypersensitivity Immune response Immunity In Vitro Inbred BALB C Mice Inflammation Mediators Interleukin-10 Malignant Neoplasms Mediating Molecular Mus Pathway interactions Phagocytosis Phosphatidylserines Production Proteins Regulation Regulatory T-Lymphocyte Relative (related person)Rheumatoid Arthritis Role Structure-Activity Relationship Susceptibility Gene T cell response T-Cell Activation T-Lymphocyte TNFRSF5 gene Th1 Cells Th1/Th2 Differentiation Pathway Tissues airway hyperresponsiveness congenic in vivo macrophage mouse model novel peripheral tolerance phosphatidylserine receptor response therapy design uptake

项目摘要

The TIM gene family was identified using a congenic mouse model in which polymorphisms in TIM-1 and TIM-3 were associated with differences in Th1-Th2 differentiation and allergen-induced airway hyperreactivity (AHR) between BALB/c and congenic HBA mice. Our goal is to understand how the Tim genes regulate peripheral tolerance, adaptive immune responses, and allergy. We have shown that TIM-1 is an important costimulatory molecule for T cells, that TIM-1 and TIM-4 regulate 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 recently 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 binding to PtdSer. These results suggest a new paradigm for TIM proteins as PtdSer receptors that by regulating the recognition, clearance, and response to apoptotic cells, can regulate T cell responses and the induction of peripheral tolerance. To understand how TIM protein recognition of PtdSer regulates immune responses, we propose to: Specific Aim 1: Determine the functional consequences of TIM-4 and TIM-3 on APC binding to phosphatidylserine on apoptotic cells. We will examine effects of apoptotic cell engulfment on DCs and macrophages including (a) anti-inflammatory mediator production: IL-10, TGF-B, IDO; (b) expression of co-inhibitory molecules; and (c) expression of co-stimulatory molecules. We will determine the effects of TIM-4- and TIM-3 mediated phagocytosis of apoptotic cell antigen on TReg and T helper subset development. Specific Aim 2. Determine the structure/function relationship of TIM allelic variants on recognition of phosphatidylserine, phagocytosis, and T cell activation. We will determine if cells expressing HBA and BALB/c alleles of TIM-1 and TIM-3 have different capacities to recognize PtdSer and phagocytose apoptotic cells. We will determine how binding of PtdSer on an apoptotic cell to TIM-1 and TIM-3 on a T cell regulates T cell activation and TReg development, and compare BALB/c and HBA T cells. Specific Aim 3: Investigate the in vivo role of TIM-1 and TIM-3 allelic variants in immune responses and regulation of peripheral tolerance. We will compare the roles of the TIM-3 pathway in clearance of apoptotic cells in vivo and in the presentation of apoptotic cell-associated antigen in BALB/c and HBA mice. We will determine the relative roles of TIM-1 and TIM-3 in regulating the development of AHR in BALB/c and HBA mice. These studies will greatly increase our understanding of the function of TIMs in the regulation of T cell responses and tolerance, and characterize a novel and extremely important asthma susceptibility gene family.

TIM 基因家族是使用同源小鼠模型进行鉴定的，其中 TIM-1 和 TIM-1 的多态性 TIM-3 与 Th1-Th2 分化和过敏原诱导的气道高反应性差异相关 BALB/c 和同类 HBA 小鼠之间的 (AHR)。我们的目标是了解 Tim 基因如何调节外周耐受、适应性免疫反应和过敏。我们已经证明 TIM-1 是一种重要的 T 细胞的共刺激分子，TIM-1 和 TIM-4 调节 T 细胞反应和发育 TIM-1 和 TIM-4 是磷脂酰丝氨酸 (PtdSer) 的受体，磷脂酰丝氨酸是耐受性的关键分子凋亡细胞的识别和摄取。我们最近发现 TIM-3 在 Th1 细胞上表达 APC 也是 PtdSer 的受体，与哮喘相关的 TIM-3 等位基因变体在结合方面有所不同到 PtdSer。这些结果提出了 TIM 蛋白作为 PtdSer 受体的新范例，通过调节对凋亡细胞的识别、清除和反应，可以调节 T 细胞反应和诱导外周耐受性。为了了解 PtdSer 的 TIM 蛋白识别如何调节免疫反应，我们建议：具体目标 1：确定 TIM-4 和 TIM-3 对 APC 结合的功能影响磷脂酰丝氨酸对凋亡细胞的作用。我们将检查凋亡细胞吞噬对 DC 的影响巨噬细胞包括(a)产生抗炎介质：IL-10、TGF-B、IDO； (b) 共抑制的表达分子； (c)共刺激分子的表达。我们将确定 TIM-4 的效果- TIM-3 介导对 TReg 和 T 辅助子亚群发育的凋亡细胞抗原的吞噬作用。具体目标 2. 确定 TIM 等位基因变体识别时的结构/功能关系磷脂酰丝氨酸、吞噬作用和 T 细胞激活。我们将确定细胞是否表达 HBA 和 TIM-1和TIM-3的BALB/c等位基因具有不同的识别PtdSer和吞噬细胞凋亡的能力细胞。我们将确定凋亡细胞上的 PtdSer 与 T 细胞上的 TIM-1 和 TIM-3 的结合如何调节 T 细胞活化和 TReg 发育，并比较 BALB/c 和 HBA T 细胞。具体目标 3：研究 TIM-1 和 TIM-3 等位基因变体在免疫反应中的体内作用和外周耐受性的调节。我们将比较 TIM-3 通路在清除中的作用体内凋亡细胞以及 BALB/c 和 HBA 小鼠中凋亡细胞相关抗原的呈递。我们将确定TIM-1和TIM-3在调节BALB/c和AHR发展中的相对作用 HBA 小鼠。这些研究将极大地增加我们对TIMs在T细胞调节中的功能的理解反应和耐受性，并表征了一个新颖且极其重要的哮喘易感性基因家族。