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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：
8288920
负责人：
Rosemarie H DeKruyff
金额：
$ 42.74万
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/8288920
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基因家族是用小鼠基因模型鉴定的，其中TIM-1和TIM-1基因的多态性