Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
Immunohorizons. 2020 Aug 7;4(8):485-497. doi: 10.4049/immunohorizons.2000055.
The contribution of self-peptide-MHC signaling in CD4 T cells to metabolic programming has not been definitively established. In this study, we employed LLO118 and LLO56, two TCRtg CD4 T cells that recognize the same epitope. We previously have shown that LLO56 T cells are highly self-reactive and respond poorly in a primary infection, whereas LLO118 cells, which are less self-reactive, respond well during primary infection. We performed metabolic profiling and found that naive LLO118 had a dramatically higher basal respiration rate, a higher maximal respiration rate, and a higher glycolytic rate relative to LLO56. The LLO118 cells also exhibited a greater uptake of 2-NBD-glucose, in vitro and in vivo. We extended the correlation of low self-reactivity (CD5) with high basal metabolism using two other CD4 TCRtg cells with known differences in self-reactivity, AND and Marilyn. We hypothesized that the decreased metabolism resulting from a strong interaction with self was mediated through TCR signaling. We then used an inducible knock-in mouse expressing the Scn5a voltage-gated sodium channel. This channel, when expressed in peripheral T cells, enhanced basal TCR-mediated signaling, resulting in decreased respiration and glycolysis, supporting our hypothesis. Genes and metabolites analysis of LLO118 and LLO56 T cells revealed significant differences in their metabolic pathways, including the glycerol phosphate shuttle. Inhibition of this pathway reverts the metabolic state of the LLO118 cells to be more LLO56 like. Overall, these studies highlight the critical relationship between peripheral TCR-self-pMHC interaction, metabolism, and the immune response to infection.
自身肽-MHC 信号在 CD4 T 细胞中的代谢编程中的作用尚未得到明确证实。在这项研究中，我们使用了 LLO118 和 LLO56 两种 TCRtg CD4 T 细胞，它们识别相同的表位。我们之前已经表明，LLO56 T 细胞具有高度的自身反应性，在初次感染时反应不佳，而 LLO118 细胞反应性较低，在初次感染时反应良好。我们进行了代谢谱分析，发现与 LLO56 相比，幼稚的 LLO118 具有更高的基础呼吸率、更高的最大呼吸率和更高的糖酵解率。LLO118 细胞在体外和体内也表现出更高的 2-NBD-葡萄糖摄取。我们使用另外两种具有已知自身反应性差异的 CD4 TCRtg 细胞 AND 和 Marilyn，扩展了低自身反应性（CD5）与高基础代谢之间的相关性。我们假设，与自身的强烈相互作用导致代谢降低是通过 TCR 信号传导介导的。然后，我们使用表达 Scn5a 电压门控钠通道的可诱导敲入小鼠。当该通道在外周 T 细胞中表达时，增强了基础 TCR 介导的信号传导，导致呼吸和糖酵解降低，支持我们的假设。LLO118 和 LLO56 T 细胞的基因和代谢物分析显示，它们的代谢途径存在显著差异，包括甘油磷酸穿梭。抑制该途径可使 LLO118 细胞的代谢状态恢复得更像 LLO56。总的来说，这些研究强调了外周 TCR-自身 pMHC 相互作用、代谢和对感染的免疫反应之间的关键关系。
