OX40共刺激信号在肥胖诱导的脂肪组织炎症和胰岛素抵抗中的作用

Increased obesity, and associated metabolic disease, has become one of the most significant public health issues in the modern era. Chronic adipose inflammation links obesity to its metabolic complications. Recent studies indicated that adipose T cells partner with adipose tissue macrophages to cause inflammation and insulin resistance. Targeting inflammatory T cells, Th1 and CD8+ T cells, by genetic approaches or depletion of T cell populations with antibodies significantly improves obesity-induced insulin resistance. Our limited understanding of mechanism(s) in obesity-induced adipose T cell activation impedes the development of an effective and specific means to uncouple obesity from its negative effects on health. .It is known that T cell activation requires major histocompatibility complex (MHC) mediated antigen presentation and costimulation. While MHC participates in cell activation in almost all T cell mediated immune responses, individual members of the large family of costimulators plays specific roles in certain immune responses. This diversity of costimulators makes them attractive therapeutic targets in immune-related diseases. We previously showed that adipocyte MHC class II (MHCII) plays an essential role in obesity-induced CD4+ adipose T cell activation and insulin resistance and other groups have shown that adipose tissue macrophage (ATM) MHCII may play a similar role. We have now completed a T cell costimulator gene expression profile in adipocytes and ATMs from lean and obese mice. We found that OX40 ligand (OX40L) is the most profoundly upregulated T cell costimulator in both cell types during obesity. Importantly, OX40L levels are also increased in adipocytes from obese and insulin resistant human patients. Because OX40L only binds to a single receptor, OX40, we tested adipose inflammation and insulin sensitivity in OX40-/- mice and found marked attenuation of activation of Th1 and CD8+ T cells in adipose tissue and significantly improvements in insulin resistance on high fat diet. Based on these results, we hypothesize that OX40L-OX40 costimulation mediates obesity-induced activation of adipose Th1 and CD8+ T cells and therefore promotes insulin resistance. We now propose to test this hypothesis using a variety of cellular and genetic techniques. We will use genetic loss- and gain-of function approaches to determine if OX40L is necessary and sufficient for adipose T cell activation and insulin resistance in a diet-induced obesity mouse model. We will also investigate mechanisms by which adipose Th1 and CD8+ T cells are reduced in obese OX40-/- mice and determine whether improved insulin sensitivity in OX40-/- mice results from reduced adipose Th1 and CD8+ T cells. Finally, we will test if OX40L blocking antibody prevents or ameliorates obesity-induced inflammation and insulin resistance. Together, these approaches will reveal whether OX40L/OX40 costimulation plays a critical role in obesity-induced inflammation and insulin resistance and, since safe OX40L blocking antibodies are available, could lead to new clinical strategies to dissociate obesity from its complications by inhibiting activation of adipose T cells.

脂肪组织中的炎性T细胞促进脂肪组织炎症和胰岛素抵抗的发生。目前脂肪组织中T细胞的激活机制仍然不明确。 T细胞的激活需要主要组织相容性复合体（MHC）呈递抗原和共刺激因子活化这两个关键步骤。在特定的免疫应答过程中，共刺激分子超家族中某些特定成员发挥着尤其重要的作用。共刺激分子的多样性使其成为治疗免疫相关性疾病的一种重要靶点。在肥胖引起的T细胞激活和胰岛素抵抗发生过程中，MHCII分子起着重要的作用。本项目前期研究发现，在肥胖小鼠脂肪组织中，OX40配体（OX40L）是上调最明显的T细胞共刺激分子。 我们将使用脂肪细胞和巨噬细胞特异性敲除OX40L的小鼠来确证OX40L对脂肪组织炎症和胰岛素抵抗的作用，同时探索OX40L调控脂肪组织T细胞活化机制，最后检测OX40L阻断抗体对脂肪组织炎症和胰岛素敏感性的作用。我们的研究将更深入认识脂肪组织炎症发生机制，为特异性抑制脂肪组织炎症提供新靶点。

脂肪组织中的炎性T细胞促进脂肪组织炎症和胰岛素抵抗的发生。目前脂肪组织中T细胞的激活机制仍然不明确。T细胞的激活需要主要组织相容性复合体（MHC）呈递抗原和共刺激因子活化这两个关键步骤。在特定的免疫应答过程中，共刺激分子超家族中某些特定成员发挥着尤其重要的作用。共刺激分子的多样性使其成为治疗免疫相关性疾病的一种重要靶点。在肥胖引起的T细胞激活和胰岛素抵抗发生过程中，MHCII分子起着重要的作用。我们的研究发现，在肥胖小鼠脂肪组织中，OX40配体（OX40L）是上调最明显的T细胞共刺激分子。在本项目中我们利用脂肪细胞和巨噬细胞特异性敲除OX40L的小鼠来研究OX40L对脂肪组织炎症和胰岛素抵抗的作用，同时探索OX40L调控脂肪组织T细胞活化机制，最后检测OX40L阻断抗体对脂肪组织炎症和胰岛素敏感性的作用。结果表明，脂肪细胞OX40L在肥胖诱导的脂肪炎症和胰岛素抵抗中起关键作用，同时发现OX40-/-小鼠中脂肪组织的Th1和CD8+ T细胞数量下降有助于改善胰岛素敏感性，而且OX40L阻断抗体能预防肥胖诱导的脂肪组织T细胞活化和胰岛素抵抗。在关注脂肪细胞中特异性敲除OX40L小鼠脂肪组织中CD8+ T细胞和Th1细胞的变化时发现，脂肪组织中Treg的数量显著下降，相关的机制正在研究。我们的研究将更深入认识脂肪组织炎症发生机制，为特异性抑制脂肪组织炎症提供新靶点。