JAML: A New Costimulatory Molecule for Gamma Delta T Cells

JAML：Gamma Delta T 细胞的新型共刺激分子

• 批准号: 8468977
• 负责人: Wendy L. Havran
• 金额: $ 54.78万
• 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/8468977
• 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.

描述（由申请人提供）：我们最近鉴定了一种上皮gd T细胞特异性共刺激分子，连接粘附分子样蛋白（JAML）。 JAML 与其配体柯萨奇和腺病毒受体 (CAR) 的结合提供了共刺激，导致细胞增殖以及细胞因子和生长因子的产生。抑制 JAML 共刺激会导致 gd T 细胞活化减少和伤口闭合延迟，类似于没有 gd T 细胞的情况。我们假设 JAML-CAR 相互作用在组织稳态中发挥关键作用，并且 JAML-CAR 表达和功能在慢性伤口患者中失调。有趣的是，小鼠和慢性伤口患者的表皮 gd T 细胞在功能上均无反应。缺乏 JAML 的共刺激可能会导致 T 细胞无反应，导致 T 细胞对愈合的贡献有缺陷。如果有责任的话，JAML 和 CAR 分子将成为加速伤口愈合的治疗干预的可能目标。在开发临床应用之前，必须确定 JAML-CAR 相互作用如何促进 gd T 细胞激活，并了解更多有关调节这些分子功能的机制。我们将确定 JAML-CAR 相互作用共同刺激 DETC 的机制。我们将确定小鼠皮肤稳态期间是否需要 JAML-CAR 相互作用，以及 JAML 信号传导缺陷是否会导致慢性伤口中出现的 T 细胞无反应。我们将研究 JAML-CAR 相互作用对人表皮 gd T 细胞功能的贡献，并确定慢性伤口中的表达是否失调。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 细胞激活的新范例，并确定针对 JAML-CAR 共刺激途径以改善慢性伤口愈合的机制和策略。