Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China.
Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, China.
Front Immunol. 2018 Sep 12;9:1940. doi: 10.3389/fimmu.2018.01940. eCollection 2018.
As a critical linker between mTORC1 and mTORC2, Akt is important for the cell metabolism. The role of Akt in the function and development of B and T cells is well characterized, however, the role of Akt for development and function of iNKT cells is unknown. iNKT cells bridge the adaptive and innate immunity, and in this study, we found that the differentiation of NKT17 cells and IL17 production of NKT17 cells were disrupted in Akt2 KO mice. ICOS has been demonstrated to be critical for the differentiation of NKT17 cells and we found that ICOS mRNA and protein expression was reduced in Akt2 KO iNKT cells. As a consequence, phosphorylation of FoxO-1 was downregulated in Akt2 KO thymocytes but the sequestration of FoxO-1 in the nucleus of Akt2 KO iNKT cells was increased. The negative feedback loop between ICOS and FoxO-1 has been demonstrated in CD4T follicular helper cells. Therefore our study has revealed a new intracellular mechanism in which Akt2 regulates ICOS expression via FoxO-1 and this signaling axis regulates the differentiation and function of NKT17 cells. This study provides a new linker between cell metabolism and function of iNKT cells.
作为 mTORC1 和 mTORC2 的关键连接物，Akt 对于细胞代谢非常重要。Akt 在 B 和 T 细胞的功能和发育中的作用已经得到很好的描述，然而，Akt 对于 iNKT 细胞的发育和功能的作用尚不清楚。iNKT 细胞连接了适应性免疫和固有免疫，在这项研究中，我们发现在 Akt2 KO 小鼠中，NKT17 细胞的分化和 NKT17 细胞的 IL17 产生受到了破坏。ICOS 已被证明对 NKT17 细胞的分化至关重要，我们发现 Akt2 KO iNKT 细胞中的 ICOS mRNA 和蛋白表达减少。结果，FoxO-1 的磷酸化在 Akt2 KO 胸腺细胞中下调，但 Akt2 KO iNKT 细胞中 FoxO-1 的核内隔离增加。ICOS 和 FoxO-1 之间的负反馈循环已在 CD4T 滤泡辅助细胞中得到证实。因此，我们的研究揭示了 Akt2 通过 FoxO-1 调节 ICOS 表达的新的细胞内机制，该信号轴调节 NKT17 细胞的分化和功能。这项研究为细胞代谢和 iNKT 细胞功能之间提供了一个新的连接。
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