TIM recognition of phosphatidylserine regulates innate and adaptive immunity

TIM 识别磷脂酰丝氨酸调节先天性和适应性免疫

• 批准号: 8676628
• 负责人: Gordon James Freeman
• 金额: $ 117.97万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676628
• 关键词: Affect; Antigen-Presenting Cells; Apoptotic; Asthma; Atopic Dermatitis; Binding; Biochemistry; Cells; Cellular Immunology; Cessation of life; Congenic Mice; Disease; Disease susceptibility; Epitopes; Family; Food Hypersensitivity; Gene Family; Genes; Genetic Polymorphism; Goals; Grant; Hepatitis; Hypersensitivity; Immune Tolerance; Immune response; Immunity; Instruction; Lead; Ligand Binding; Ligands; Liver; Lung; Modeling; Molecular; Molecular Immunology; Monkeys; Mucosal Immune Responses; Mus; Natural Immunity; Pattern; Pattern recognition receptor; Phase; Phosphatidylserines; Play; Proteins; Reagent; Rheumatoid Arthritis; Role; Seminal; Structure; Susceptibility Gene; T-Lymphocyte; Transgenic Organisms; adaptive immunity; improved; in vivo Model; killer T cell; novel; oral tolerance; phosphatidylserine receptor; positional cloning; programs; respiratory; structural biology; virology

The overall goal of these studies is to understand how the HM genes regulate immune responses. The TIM gene family, discovered by our group in 2001 using a positional cloning strategy in congenic mice, potently regulates innate and adaptive immune responses. In the previous grant period, we showed that TIM-1 is an important costimulatory molecule for T cells and an important susceptibility gene for atopic diseases, and that TIM-4 and TIM-1 function as receptors for phosphatidylserine (PtdSer). a critical marker of apoptotic cells. The current Program Project builds on these seminal findings, and consists of four interconnected and complementary Projects focusing on different aspects of TIM interactions with PtdSer expressed by apoptotic cells. The overall hypothesis is that the TIMs function as pattern recognition receptors that sense PtdSer as a DAMP (damage associated molecular pattern), and that the TIMs function either to clear apoptotic cells or to amplify immunity by responding to apoptotic/dying cells. In Project 1, we will study TIM-1 expressing natural killer T (NKT) cells, which function to sense and become activated by apoptotic cells in the liver and in the lungs. In Project 2, we will examine intracellular, molecular and functional consequences of PtdSer on apoptotic cells binding to TIM molecules on antigen presenting cells (APCs) and T cells. In Project 3 we will examine the role of TIMs in in vivo models of respiratory and oral tolerance, in which clearance of apoptotic cells by TIM expressing APCs plays a critical role. In Project 4 we will examine the structure of TIM proteins and the influence ofthe TIM gene polymorphisms on ligand recognition and presentation of ligand binding epitopes. Our Projects utilize unique reagents, including TIM specific mAbs, TIM-1 transgenic, TIM-4 transgenic and TIM-I"'' and TIM-3"'" mice, TIM crystals, monkeys and complementary approaches involving crystallogra¿¿ phy, structural biology, virology, biochemistry as well as cellular and molecular immunology, in models of asthma, hepatitis, respiratory tolerance and oral tolerance. Our studies will demonstrate that the T/Mgene family evolved to sense the presence of apoptotic cells at different phases of immunity, and to play a major role in regulating distinct compartments of mucosal immune responses by affecting cell activation, survival, death and immune tolerance. The results of these studies will greatly impact our understanding of immunity, and may lead to important new therapies for inflammatorv diseases, including asthma and food allergy. RELEVANCE (See instructions): The 7//W genes have been shown to be important disease susceptibility genes (asthma, allergy, atopic dermatitis, food allergy and rheumatoid arthritis) and to potently regulate immune responses. We believe that further study of these molecules will greatly improve our understanding of disease mechanisms, and are likely to lead to novel therapies for asthma and food allergy.

这些研究的总体目标是了解HM基因如何调节免疫反应。TIM

项目成果

T-cell immunoglobulin and mucin domain 1 deficiency eliminates airway hyperreactivity triggered by the recognition of airway cell death.

• DOI: 10.1016/j.jaci.2013.03.025
• 发表时间: 2013-08
• 期刊: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
• 影响因子: 14.2
• 作者: Kim, Hye Young;Chang, Ya-Jen;Chuang, Ya-Ting;Lee, Hyun-Hee;Kasahara, David I.;Martin, Thomas;Hsu, Joyce T.;Savage, Paul B.;Shore, Stephanie A.;Freeman, Gordon J.;DeKruyff, Rosemarie H.;Umetsu, Dale T.
• 通讯作者: Umetsu, Dale T.

Structures of T Cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family.

• DOI: 10.1016/j.immuni.2007.01.014
• 发表时间: 2007-03
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Santiago C;Ballesteros A;Tami C;Martínez-Muñoz L;Kaplan GG;Casasnovas JM
• 通讯作者: Casasnovas JM

TIM-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine.

• DOI: 10.1371/journal.ppat.1003232
• 发表时间: 2013-03
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Jemielity S;Wang JJ;Chan YK;Ahmed AA;Li W;Monahan S;Bu X;Farzan M;Freeman GJ;Umetsu DT;Dekruyff RH;Choe H
• 通讯作者: Choe H

Reply to Das et al., "TIM1 (HAVCR1): an Essential 'Receptor' or an 'Accessory Attachment Factor' for Hepatitis A Virus?"

回复 Das 等人，“TIM1 (HAVCR1)：甲型肝炎病毒的重要‘受体’还是‘辅助附着因子’？”

• DOI: 10.1128/jvi.02040-18
• 发表时间: 2019
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Costafreda,MariaIsabel;Kaplan,Gerardo
• 通讯作者: Kaplan,Gerardo

Innate lymphoid cells in asthma: Will they take your breath away?

• DOI: 10.1002/eji.201444557
• 发表时间: 2016-04
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Kim HY;Umetsu DT;Dekruyff RH
• 通讯作者: Dekruyff RH