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: 7949426
• 负责人: Rosemarie H DeKruyff
• 金额: $ 42.83万
• 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/7949426
• 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; Doctor of Philosophy; 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; anticancer research; congenic; in vivo; macrophage; mouse model; novel; peripheral tolerance; phosphatidylserine receptor; public health relevance; receptor; 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基因家族是使用同源小鼠模型鉴定的，其中TIM-1和TIM-3的多态性与BALB/之间Th1-Th2分化和过敏原诱导的气道高反应性（AHR）的差异相关。 c和同类HBA小鼠。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，并且TIM-1和TIM-4是磷脂酰丝氨酸（PtdSer）的受体，识别和摄取凋亡细胞的关键分子。我们最近发现，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 等位基因变体在与 PtdSer 的结合方面有所不同。这些结果表明 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。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 与凋亡细胞上磷脂酰丝氨酸结合的功能影响。我们将检查凋亡细胞吞噬对 DC 和巨噬细胞的影响，包括 (a) 抗炎介质产生：IL-10、TGF-2、IDO； (b)共抑制分子的表达； (c)共刺激分子的表达。我们将确定 TIM-4 和 TIM-3 介导的凋亡细胞抗原吞噬作用对 TReg 和 T 辅助子亚群发育的影响。 具体目标 2. 确定 TIM 等位基因变体对磷脂酰丝氨酸识别、吞噬作用和 T 细胞激活的结构/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 的结合如何调节 T 细胞激活和 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和外周耐受调节中的体内作用。我们将比较 TIM-3 通路在体内清除凋亡细胞以及 BALB/c 和 HBA 小鼠中凋亡细胞相关抗原呈递中的作用。我们将确定 TIM-1 和 TIM-3 在调节 BALB/c 和 HBA 小鼠 AHR 发育中的相对作用。 这些研究将大大增加我们对 TIM 在 T 细胞反应和耐受调节中的功能的理解，并表征一个新颖且极其重要的哮喘易感性基因家族。 公共健康相关性：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），并能有效调节免疫反应和外周耐受性。 TIM 蛋白识别死亡细胞并帮助将其从体内清除。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出治疗哮喘、过敏、自身免疫性疾病和癌症的疗法。