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

• 批准号: 8082683
• 负责人: Rosemarie H DeKruyff
• 金额: $ 42.68万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 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/8082683
• 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; public health relevance; response; therapy design; uptake

DESCRIPTION (provided by applicant): 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-2, 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. PUBLIC HEALTH RELEVANCE: The TIM genes have been shown to be important disease susceptibility genes (asthma, allergy, atopic dermatitis, rheumatoid arthritis) and to potently regulate immune responses and peripheral tolerance. TIM proteins recognize dead cells and help remove them from the body. Increased understanding of how TIM proteins regulate immune responses will allow us to design therapies for asthma, allergies, autoimmune disease and cancer.

描述(由申请人提供)：TIM基因家族是通过同源小鼠模型鉴定的，在该模型中，TIM-1和TIM-3的多态与BALB/c和同源HBA小鼠之间Th1-Th2分化和变应原诱导的呼吸道高反应性(AHR)的差异有关。我们的目标是了解TIM基因是如何调节外周耐受、适应性免疫反应和过敏的。我们已经证明TIM-1是T细胞重要的共刺激分子，TIM-1和TIM-4调节T细胞的反应和耐受的形成，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。我们最近发现，表达在Th1细胞和APC上的Tim-3也是PtdSer的受体，而且与哮喘相关的TIM-3的等位基因变体与PtdSer的结合不同。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、清除和反应，可以调节T细胞的反应和诱导外周耐受。为了了解PtdSer的Tim蛋白识别如何调节免疫反应，我们建议：特定目标1：确定Tim-4和Tim-3对APC与磷脂酰丝氨酸结合的功能影响。我们将研究凋亡细胞吞噬DC和巨噬细胞的影响，包括：(A)抗炎介质的产生：IL-10、转化生长因子-2、IDO；(B)共抑制分子的表达；以及(C)共刺激分子的表达。我们将确定TIM-4和TIM-3介导的吞噬凋亡细胞抗原对Treg和T辅助细胞亚群发育的影响。特定目的2.确定TIM等位基因突变体在识别磷脂酰丝氨酸、吞噬功能和T细胞激活方面的结构/功能关系。我们将确定表达TIM-1和TIM-3的HBA和BALB/c等位基因的细胞是否具有不同的识别PtdSer和吞噬凋亡细胞的能力。我们将确定凋亡细胞上的PtdSer与T细胞上的Tim-1和Tim-3结合如何调节T细胞的激活和Treg的发育，并比较BALB/c和HBA T细胞。特异性目标3：研究TIM-1和TIM-3等位基因在免疫应答和外周免疫耐受调节中的作用。我们将比较TIM-3通路在体内清除凋亡细胞以及在BALB/c和HBA小鼠中呈递凋亡细胞相关抗原中的作用。我们将确定TIM-1和TIM-3在调节BALB/c和HBA小鼠AHR发生中的相对作用。这些研究将极大地加深我们对TIMs在调节T细胞反应和耐受中的功能的理解，并描述一个新的和极其重要的哮喘易感基因家族。 公共卫生相关性：TIM基因已被证明是重要的疾病易感基因(哮喘、过敏、特应性皮炎、类风湿性关节炎)，并有效地调节免疫反应和外周耐受。TIM蛋白识别死亡细胞，并帮助将它们从体内清除。加深对TIM蛋白如何调节免疫反应的了解，将使我们能够设计治疗哮喘、过敏、自身免疫性疾病和癌症的方法。