脂联素新型免疫受体的发现及其调节T细胞的分子机制研究

In order to prevent uncontrolled inflammation or autoimmune response, it is important to fine-tune the immune response and govern it to a proper state. Adiponectin (APN) is the most abundant adipokines in human’s plasma, with a collagen domain in its N-terminal. Although, it has been reported that APN plays a role in inhibiting inflammatory response, the way of APN interacts with immune cells and the molecular mechanism of its immune suppressive effect are still elusive. Collagen is considered as a high-affinity ligand to the LAIR-1 (leukocyte-associated Ig-like receptor), which is an inhibitory receptor expressed on most immune cells surface and negatively regulates immune response. In our previous study, we found that APN could restrain the expression of IL-2 in Jurkat T cells. We have also demonstrated that APN protein could interact with LAIR-1 protein on Jurkat T cells. In this project, we will further confirm the new receptor-ligand relationship between APN and LAIR-1. Based on this, we will then clarify the molecular mechanism underlying the way by which APN suppresses the expression of IL-2 via LAIR-1, especially through its downstream SHP and ZAP-70 pathway. Our study could not only give us a better understanding on the way of how APN acts on immune cells via its newly found immune receptor, but also provide us clues for the intervention strategies of some immune related diseases.

精确调控免疫应答对于防止不可控的炎症反应以及自身免疫性疾病有重要的意义。脂联素是血浆中含量最高的脂肪因子，其抑制炎症反应的作用已被广泛报道，但关于脂联素如何直接作用于免疫细胞并发挥免疫抑制功能的机制尚未明晰。脂联素N-端含有胶原结构域，而胶原被认为是免疫抑制分子白细胞相关免疫球蛋白样受体-1（LAIR-1）的高亲和力配体，与免疫细胞表面的LAIR-1结合后可发挥免疫负调控的作用。我们前期研究发现具有胶原结构域的脂联素不仅可抑制Jurkat T细胞产生IL-2并可与LAIR-1结合。本项目拟在证实LAIR-1是脂联素新受体的基础上，进一步阐明脂联素通过LAIR-1发挥抑制T细胞产生活化的分子机制，尤其是脂联素结合LAIR-1后其下游SHP磷酸酶的活化作用以及对T细胞活化中ZAP-70等关键信号转导分子的作用，加深对脂联素对免疫细胞直接作用的认识，并为某些免疫相关疾病的干预策略提供新线索。

脂联素(Adiponectin，APN)是人血浆中含量最丰富的脂肪因子，并具有胰岛素增敏、抗动脉粥样硬化、抗炎等作用。最近的研究报道，APN在不同情况下同时发挥抗炎和促炎作用。然而，并没有充足的证据证实已知的APN受体及其下游信号通路介导了APN的抗炎作用。本课题中，我们研究了APN抗炎作用的新分子机制。基于蛋白和细胞的实验结果显示，脂联素的球状结构域(gAdp)与免疫细胞表面广泛表达的抑制性白细胞相关免疫球蛋白样受体-1(LAIR-1)相互作用。随后的体外细胞实验结果显示，gAdp通过LAIR-1途径抑制T细胞的活化，下游SHP-2和ZAP-70分子参与了这一过程。这些发现表明LAIR-1是一种新的APN受体，肯定了APN的抗炎作用。总的来说，我们确定了外周免疫调节过程的新机制，为进一步研究gAdp在炎症相关疾病中的作用提供了基础。