JAML: A New Costimulatory Molecule for Gamma Delta T Cells

描述（由申请人提供）：我们最近发现了一种上皮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）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共刺激导致gd T细胞活化减少和伤口愈合延迟，类似于没有gd T细胞时的情况。我们假设JAML-CAR相互作用在组织稳态中起关键作用，并且JAML-CAR的表达和功能在慢性伤口患者中失调。有趣的是，在小鼠和慢性伤口患者中，表皮gd - T细胞在功能上都没有反应。通过JAML缺乏共刺激可能导致T细胞能量不足，导致T细胞对愈合的贡献有缺陷。如果有责任，JAML和CAR分子将成为加速伤口愈合的治疗干预的可能目标。在临床应用开发之前，必须确定JAML- CAR相互作用如何促进gd T细胞活化，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稳态过程中是否需要JAML- car相互作用，以及JAML信号缺陷是否导致慢性伤口中的T细胞无反应性。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，并确定慢性伤口中表达是否失调。在小鼠模型和人类慢性伤口中，我们将采用调节JAML-CAR表达的策略来加速伤口愈合。总之，本研究中获得的信息将有助于开发上皮细胞T细胞活化的新范例，并确定靶向jjam - car共刺激途径以改善慢性伤口愈合的机制和策略。

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.