JAML: A New Costimulatory Molecule for Gamma Delta T Cells

描述(申请人提供)：我们最近发现了一种上皮细胞特异性共刺激分子，连接黏附分子样蛋白(JAML)。JAML与其配体Coxsackie和腺病毒受体(CAR)结合提供共刺激，导致细胞增殖和细胞因子和生长因子的产生。抑制JAML共刺激会导致gd T细胞活化减弱和伤口延迟愈合，与没有gd T细胞时的情况类似。我们假设JAML-CAR相互作用在组织动态平衡中起关键作用，JAML-CAR的表达和功能在慢性创面患者中调节失调。有趣的是，无论是小鼠还是慢性创面患者，表皮GdT细胞在功能上都是无反应的。缺乏通过JAML的共刺激可能导致T细胞无能，从而导致缺陷的T细胞对修复的贡献。如果负责任，JAML和CAR分子将成为促进伤口愈合的治疗干预的可能目标。在开发临床应用之前，有必要确定JAML-CAR相互作用如何促进gd T细胞激活，并了解更多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。我们将确定在小鼠皮肤的动态平衡过程中是否需要JAML-CAR相互作用，以及JAML信号的缺陷是否导致慢性伤口中出现的T细胞无反应。我们将研究JAML-CAR相互作用对人类表皮gd T细胞功能的贡献，并确定在慢性伤口中是否存在表达失调。将采用策略来调节JAML-CAR的表达，以加速小鼠模型和人类慢性伤口的伤口愈合。总之，这项研究获得的信息将有助于开发一种新的上皮gd T细胞激活模式，并确定针对JAML-CAR共刺激途径的机制和策略，以促进慢性伤口的愈合。

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.