Pan Youdong, Tian Tian, Park Chang Ook, Lofftus Serena Y, Mei Shenglin, Liu Xing, Luo Chi, O'Malley John T, Gehad Ahmed, Teague Jessica E, Divito Sherrie J, Fuhlbrigge Robert, Puigserver Pere, Krueger James G, Hotamisligil Gökhan S, Clark Rachael A, Kupper Thomas S
Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA.
Department of Biostatistics and Computational Biology, Center for Functional Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Nature. 2017 Mar 9;543(7644):252-256. doi: 10.1038/nature21379. Epub 2017 Feb 20.
Tissue-resident memory T (T) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens. However, the biological pathways that enable the long-term survival of T cells are obscure. Here we show that mouse CD8 T cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5). We further show that T-cell-specific deficiency of Fabp4 and Fabp5 (Fabp4/Fabp5) impairs exogenous free fatty acid (FFA) uptake by CD8 T cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (T) cells in lymph nodes. In vitro, CD8 T cells, but not CD8 T cells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4/Fabp5 double-knockout CD8 T cells. The persistence of CD8 T cells in the skin was strongly diminished by inhibition of mitochondrial FFA β-oxidation in vivo. Moreover, skin CD8 T cells that lacked Fabp4/Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4/Fabp5 double-knockout CD8 T cells generated by skin vaccinia virus (VACV) infection were less effective at protecting mice from a lethal pulmonary challenge with VACV. Consistent with the mouse data, increased FABP4 and FABP5 expression and enhanced extracellular FFA uptake were also demonstrated in human CD8 T cells in normal and psoriatic skin. These results suggest that FABP4 and FABP5 have a critical role in the maintenance, longevity and function of CD8 T cells, and suggest that CD8 T cells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity.
组织驻留记忆性T（Trm）细胞在上皮屏障组织中无限期持续存在，并保护宿主抵御病原体。然而，使Trm细胞长期存活的生物学途径尚不清楚。在此，我们表明，皮肤病毒感染产生的小鼠CD8 Trm细胞差异表达高水平的几种介导脂质摄取和细胞内运输的分子，包括脂肪酸结合蛋白4和5（FABP4和FABP5）。我们进一步表明，Fabp4和Fabp5（Fabp4/Fabp5）的T细胞特异性缺陷会损害CD8 Trm细胞对外源游离脂肪酸（FFA）的摄取，并大大降低其在体内的长期存活，而对淋巴结中中央记忆性T（Tcm）细胞的存活没有影响。在体外，CD8 Trm细胞而非CD8 Tcm细胞在存在外源FFA的情况下表现出线粒体氧化代谢增加；在Fabp4/Fabp5双敲除CD8 Trm细胞中未观察到这种增加。体内线粒体FFAβ氧化的抑制强烈降低了CD8 Trm细胞在皮肤中的持久性。此外，缺乏Fabp4/Fabp5的皮肤CD8 Trm细胞在保护小鼠免受皮肤病毒感染方面效果较差，并且皮肤牛痘病毒（VACV）感染产生的肺Fabp4/Fabp5双敲除CD8 Trm细胞在保护小鼠免受VACV致死性肺部攻击方面效果较差。与小鼠数据一致，在正常和银屑病皮肤中的人CD8 Trm细胞中也证实了FABP4和FABP5表达增加以及细胞外FFA摄取增强。这些结果表明，FABP4和FABP5在CD8 Trm细胞的维持、寿命和功能中起关键作用，并表明CD8 Trm细胞利用外源FFA及其氧化代谢在组织中持续存在并介导保护性免疫。
