Douguet Laetitia, Cherfils-Vicini Julien, Bod Lloyd, Lengagne Renée, Gilson Eric, Prévost-Blondel Armelle
INSERM, U1016, Institut Cochin, Paris, France.
CNRS, UMR8104, Paris, France.
PLoS One. 2016 Nov 3;11(11):e0165639. doi: 10.1371/journal.pone.0165639. eCollection 2016.
γδ T cells play critical roles in host defense against infections and cancer. Although advances have been made in identifying γδ TCR ligands, it remains essential to understand molecular mechanisms responsible for in vivo expansion of γδ T cells in periphery. Recent findings identified the expression of the inducible NO synthase (NOS2) in lymphoid cells and highlighted novel immunoregulatory functions of NOS2 in αβ T cell differentiation and B cell survival. In this context, we wondered whether NOS2 exerts an impact on γδ T cell properties. Here, we show that γδ T cells express NOS2 not only in vitro after TCR triggering, but also directly ex vivo. Nos2 deficient mice have fewer γδ T cells in peripheral lymph nodes (pLNs) than their wild-type counterparts, and these cells exhibit a reduced ability to produce IL-2. Using chemical NOS inhibitors and Nos2 deficient γδ T cells, we further evidence that the inactivation of endogenous NOS2 significantly reduced γδ T cell proliferation and glycolysis metabolism that can be restored in presence of exogenous IL-2. Collectively, we demonstrate the crucial role of endogenous NOS2 in promoting optimal IL-2 production, proliferation and glycolysis of γδ T cells that may contribute to their regulation at steady state.
γδ T细胞在宿主抵御感染和癌症中发挥着关键作用。尽管在鉴定γδ TCR配体方面取得了进展，但了解外周血中γδ T细胞体内扩增的分子机制仍然至关重要。最近的研究发现了诱导型一氧化氮合酶（NOS2）在淋巴细胞中的表达，并突出了NOS2在αβ T细胞分化和B细胞存活中的新免疫调节功能。在此背景下，我们想知道NOS2是否会对γδ T细胞特性产生影响。在这里，我们表明γδ T细胞不仅在TCR触发后在体外表达NOS2，而且在直接离体状态下也表达。Nos2基因敲除小鼠外周淋巴结（pLNs）中的γδ T细胞比野生型小鼠少，并且这些细胞产生IL-2的能力降低。使用化学NOS抑制剂和Nos2基因敲除的γδ T细胞，我们进一步证明内源性NOS2的失活显著降低了γδ T细胞的增殖和糖酵解代谢，而在外源IL-2存在的情况下可以恢复。总的来说，我们证明了内源性NOS2在促进γδ T细胞最佳IL-2产生、增殖和糖酵解中的关键作用，这可能有助于在稳态下对它们进行调节。
