Nishimura Satoshi, Manabe Ichiro, Nagasaki Mika, Eto Koji, Yamashita Hiroshi, Ohsugi Mitsuru, Otsu Makoto, Hara Kazuo, Ueki Kohjiro, Sugiura Seiryo, Yoshimura Kotaro, Kadowaki Takashi, Nagai Ryozo
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Nat Med. 2009 Aug;15(8):914-20. doi: 10.1038/nm.1964. Epub 2009 Jul 26.
Inflammation is increasingly regarded as a key process underlying metabolic diseases in obese individuals. In particular, obese adipose tissue shows features characteristic of active local inflammation. At present, however, little is known about the sequence of events that comprises the inflammatory cascade or the mechanism by which inflammation develops. We found that large numbers of CD8(+) effector T cells infiltrated obese epididymal adipose tissue in mice fed a high-fat diet, whereas the numbers of CD4(+) helper and regulatory T cells were diminished. The infiltration by CD8(+) T cells preceded the accumulation of macrophages, and immunological and genetic depletion of CD8(+) T cells lowered macrophage infiltration and adipose tissue inflammation and ameliorated systemic insulin resistance. Conversely, adoptive transfer of CD8(+) T cells to CD8-deficient mice aggravated adipose inflammation. Coculture and other in vitro experiments revealed a vicious cycle of interactions between CD8(+) T cells, macrophages and adipose tissue. Our findings suggest that obese adipose tissue activates CD8(+) T cells, which, in turn, promote the recruitment and activation of macrophages in this tissue. These results support the notion that CD8(+) T cells have an essential role in the initiation and propagation of adipose inflammation.
炎症越来越被视为肥胖个体代谢性疾病的关键潜在过程。特别是，肥胖脂肪组织表现出活跃局部炎症的特征。然而，目前对于构成炎症级联反应的一系列事件或炎症发生的机制知之甚少。我们发现，在喂食高脂饮食的小鼠中，大量CD8(+)效应T细胞浸润到肥胖的附睾脂肪组织中，而CD4(+)辅助性T细胞和调节性T细胞的数量减少。CD8(+) T细胞的浸润先于巨噬细胞的积累，并且CD8(+) T细胞的免疫和基因清除降低了巨噬细胞浸润和脂肪组织炎症，并改善了全身胰岛素抵抗。相反，将CD8(+) T细胞过继转移到CD8缺陷小鼠中会加重脂肪炎症。共培养和其他体外实验揭示了CD8(+) T细胞、巨噬细胞和脂肪组织之间相互作用的恶性循环。我们的研究结果表明，肥胖脂肪组织激活CD8(+) T细胞，而CD8(+) T细胞反过来又促进该组织中巨噬细胞的募集和激活。这些结果支持了CD8(+) T细胞在脂肪炎症的起始和传播中起重要作用的观点。
