Mothe-Satney Isabelle, Murdaca Joseph, Sibille Brigitte, Rousseau Anne-Sophie, Squillace Raphaëlle, Le Menn Gwenaëlle, Rekima Akila, Larbret Frederic, Pelé Juline, Verhasselt Valérie, Grimaldi Paul A, Neels Jaap G
Université Côte d'Azur, Inserm, C3M, France.
INSERM U1065, Mediterranean Center of Molecular Medicine (C3M), Team 9 "Adaptive responses to immuno-metabolic dysregulations", Nice, France.
Sci Rep. 2016 Sep 29;6:34317. doi: 10.1038/srep34317.
Metabolism plays an important role in T cell biology and changes in metabolism drive T cell differentiation and fate. Most research on the role of metabolism in T lymphocytes focuses on mature T cells while only few studies have investigated the role of metabolism in T cell development. In this study, we report that activation or overexpression of the transcription factor Peroxisome Proliferator-Activated Receptor β (PPARβ) increases fatty acid oxidation in T cells. Furthermore, using both in vivo and in vitro models, we demonstrate that PPARβ activation/overexpression inhibits thymic T cell development by decreasing proliferation of CD4CD8 double-negative stage 4 (DN4) thymocytes. These results support a model where PPARβ activation/overexpression favours fatty acid- instead of glucose-oxidation in developing T cells, thereby hampering the proliferative burst normally occurring at the DN4 stage of T cell development. As a consequence, the αβ T cells that are derived from DN4 thymocytes are dramatically decreased in peripheral lymphoid tissues, while the γδ T cell population remains untouched. This is the first report of a direct role for a member of the PPAR family of nuclear receptors in the development of T cells.
代谢在T细胞生物学中发挥着重要作用，代谢变化驱动T细胞分化和命运。大多数关于代谢在T淋巴细胞中作用的研究都集中在成熟T细胞上，而只有少数研究调查了代谢在T细胞发育中的作用。在本研究中，我们报告转录因子过氧化物酶体增殖物激活受体β（PPARβ）的激活或过表达会增加T细胞中的脂肪酸氧化。此外，使用体内和体外模型，我们证明PPARβ激活/过表达通过降低CD4CD8双阴性4期（DN4）胸腺细胞的增殖来抑制胸腺T细胞发育。这些结果支持了一个模型，即PPARβ激活/过表达有利于发育中的T细胞进行脂肪酸氧化而非葡萄糖氧化，从而阻碍T细胞发育DN4阶段正常发生的增殖爆发。因此，源自DN4胸腺细胞的αβT细胞在外周淋巴组织中显著减少，而γδT细胞群体则不受影响。这是核受体PPAR家族成员在T细胞发育中直接作用的首次报道。
