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: 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
• 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

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。