JAML: A New Costimulatory Molecule for Gamma Delta T Cells

JAML：一种新的 Gamma Delta T 细胞共刺激分子

• 批准号: 8646843
• 负责人: Wendy L. Havran
• 金额: $ 54.49万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646843
• 关键词: Address; Antigens; Asthma; Binding; CAR receptor; CD28 Antigens; CD28 gene; CD8B1 gene; Cell Proliferation; Cell physiology; Cell surface; Cells; Chronic; Defect; Development; Environment; Epithelial; Growth Factor; Healed; Homeostasis; Human; Immunotherapy; Inflammatory Bowel Diseases; Langerhans cell; Lead; Learning; Ligands; MAP Kinase Gene; Maintenance; Malignant - descriptor; Modeling; Mus; Organism; Pathway interactions; Patients; Play; Population; Process; Production; Proteins; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Skin; T cell anergy; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic Intervention; Tissues; Up-Regulation; Wound Healing; clinical application; cytokine; healing; improved; junctional adhesion molecule; keratinocyte; mouse model; public health relevance; receptor expression; repaired; response; tissue repair; tumor; wound

DESCRIPTION (provided by applicant): We have recently identified an epithelial gd T cell specific costimulatory molecule, junctional adhesion molecule-like protein (JAML). Binding of JAML to its ligand Coxsackie and Adenovirus receptor (CAR) provides costimulation leading to cellular proliferation and cytokine and growth factor production. Inhibition of JAML costimulation leads to diminished gd T cell activation and delayed wound closure similar to that seen in the absence of gd T cells. We hypothesize that JAML-CAR interactions play key roles in tissue homeostasis and that JAML-CAR expression and function are dysregulated in patients with chronic wounds. Interestingly, epidermal gd T cells are functionally unresponsive in both mice and patients with chronic wounds. Lack of costimulation through JAML may lead to T cell anergy resulting in defective T cell contributions to healing. If responsible, JAML and CAR molecules would then be possible targets for therapeutic interventions to accelerate wound healing. Prior to development of clinical applications, it is essential to determine how JAML- CAR interactions contribute to gd T cell activation and learn more about mechanisms that regulate functions of these molecules. We will identify mechanisms by which JAML-CAR interactions costimulate DETC. We will determine if there is a requirement for JAML-CAR interactions during homeostasis in murine skin and if defects in JAML signaling contribute to the T cell unresponsiveness seen in chronic wounds. We will examine the contributions of JAML-CAR interactions to human epidermal gd T cell functions and determine if expression is dysregulated in chronic wounds. Strategies will be employed to modulate JAML-CAR expression to accelerate wound healing in mouse models and human chronic wounds. Together, information gained in this study will contribute to development of a new paradigm for epithelial gd T cell activation and identify mechanisms and strategies for targeting the JAML-CAR costimulatory pathway to improve healing of chronic wounds. PUBLIC HEALTH RELEVANCE: We have identified JAML as an epithelial gd T cell specific costimulatory molecule. Epithelial gd T cells play important roles in tissue homeostasis and repair. New strategies for JAML costimulation of T cells for immunotherapy could have major benefits for healing of chronic wounds as well as impact treatment of asthma, inflammatory bowel disease and epithelial tumors.

描述（由申请人提供）：我们最近鉴定了上皮gd T细胞特异性共刺激分子，连接粘附分子样蛋白（JAML）。JAML与其配体科萨基和腺病毒受体（CAR）的结合提供共刺激，导致细胞增殖和细胞因子和生长因子产生。JAML共刺激的抑制导致减少的gd T细胞活化和延迟的伤口闭合，类似于在没有gd T细胞的情况下所看到的。我们假设JAML-CAR相互作用在组织稳态中起关键作用，并且在慢性伤口患者中JAML-CAR表达和功能失调。有趣的是，表皮gd T细胞在小鼠和慢性伤口患者中功能上无反应。缺乏通过JAML的共刺激可能导致T细胞无反应性，从而导致T细胞对愈合的贡献缺陷。如果负责，JAML和CAR分子将成为治疗干预的可能目标，以加速伤口愈合。在开发临床应用之前，必须确定JAML-CAR相互作用如何有助于gd T细胞活化，并更多地了解调节这些分子功能的机制。我们将确定JAML-CAR相互作用共刺激DETC的机制。我们将确定在小鼠皮肤的稳态过程中是否需要JAML-CAR相互作用，以及JAML信号传导的缺陷是否导致慢性伤口中观察到的T细胞无反应性。我们将研究JAML-CAR相互作用对人表皮gd T细胞功能的贡献，并确定在慢性伤口中表达是否失调。将采用策略来调节JAML-CAR表达，以加速小鼠模型和人类慢性伤口的伤口愈合。总之，本研究中获得的信息将有助于开发上皮gd T细胞活化的新范例，并确定靶向JAML-CAR共刺激途径以改善慢性伤口愈合的机制和策略。 公共卫生相关性：我们已经确定JAML作为上皮gd T细胞特异性共刺激分子。上皮gd T细胞在组织稳态和修复中起重要作用。JAML共刺激T细胞用于免疫治疗的新策略可能对慢性伤口愈合以及哮喘、炎症性肠病和上皮肿瘤的影响治疗有重大益处。