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: 8704253
• 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
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704253
• 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; 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; genetic variant; 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.

使用先天小鼠模型来鉴定蒂姆基因家族，其中tim-1和tim-1和 TIM-3与Th1-Th2分化和过敏原诱导的气道高反应性的差异有关 （AHR）BALB/C和Encenic HBA小鼠之间。我们的目标是了解蒂姆基因如何调节 外围耐受性，适应性免疫反应和过敏。我们已经证明Tim-1很重要 T细胞的共刺激分子，TIM-1和TIM-4调节T细胞反应，并发展 耐受性，TIM-1和TIM-4是磷脂酰丝氨酸（PTDSER）的受体，这是一种关键分子 识别和吸收凋亡细胞。我们最近发现，TIM-3在Th1细胞和 APC也是PTDSER的受体，TIM-3的等位基因变体与哮喘有关 到ptdser。这些结果表明，TIM蛋白作为PTDSER受体的新范式，通过调节 识别，清除和对凋亡细胞的反应可以调节T细胞反应并诱导 外围耐受性。要了解Tim蛋白的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结合的功能后果 凋亡细胞上的磷脂酰丝氨酸。我们将检查凋亡细胞吞噬对DC和 巨噬细胞包括（a）抗炎介质产生：IL-10，TGF-B，IDO； （b）共抑制性的表达 分子； （c）共刺激分子的表达。我们将确定tim-4-的影响 TIM-3介导的Treg和T辅助子集发育中凋亡细胞抗原的吞噬作用。 具体目标2。确定tim等位基因变体在识别的结构/功能关系 磷脂酰丝氨酸，吞噬作用和T细胞活化。我们将确定表达HBA和 TIM-1和TIM-3的BALB/C等位基因具有不同的能力来识别PTDSER和吞噬凋亡 细胞。我们将确定PTDSER在凋亡细胞上与TIM-1和TIM-3的结合如何调节T细胞 细胞激活和Treg发育，并比较BALB/C和HBA T细胞。 特定目标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 和外围耐受性的调节。我们将比较tim-3途径的角色 BALB/C和HBA小鼠中凋亡细胞相关抗原的体内凋亡细胞。 我们将确定TIM-1和TIM-3在调节BALB/C中AHR的发展中的相对作用，并且 HBA老鼠。 这些研究将大大增加我们对TIM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为重要的哮喘敏感性基因家族。

项目成果

Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers.

• DOI: 10.18632/oncotarget.9076
• 发表时间: 2016-05-31
• 期刊: Oncotarget
• 作者: Derks S;Liao X;Chiaravalli AM;Xu X;Camargo MC;Solcia E;Sessa F;Fleitas T;Freeman GJ;Rodig SJ;Rabkin CS;Bass AJ
• 通讯作者: Bass AJ

A new therapeutic strategy for malaria: targeting T cell exhaustion.

• DOI: 10.1038/ni.2211
• 发表时间: 2012-01-19
• 期刊: Nature immunology
• 影响因子: 30.5
• 作者: Freeman GJ;Sharpe AH
• 通讯作者: Sharpe AH