Institut National de la Recherche Scientifique (INRS)-Centre Armand-Frappier Santé Biotechnologie, Laval, Quebec, Canada.
Metabolomics Innovation Resource, Rosalind and Morris Goodman Cancer Center, McGill University, Montreal, QC, Canada.
Autophagy. 2022 Jun;18(6):1256-1273. doi: 10.1080/15548627.2021.1972403. Epub 2021 Oct 6.
The maintenance of a strong IL21 production in memory CD4 T cells, especially in HIV-1-specific cells, represents a major correlate of natural immune protection against the virus. However, the molecular mechanisms underlying IL21 production during HIV-1 infection, which is only elevated among the naturally protected elite controllers (EC), are still unknown. We recently found out that lipophagy is a critical immune mediator that control an antiviral metabolic state following CD8A T cell receptor engagement, playing an important role in the natural control of HIV-1 infection. This led us to investigate whether the beneficial role of a strong macroautophagy/autophagy, could also be used to ensure effective IL21 production as well. Herein, we confirm that after both polyclonal and HIV-1-specific activation, memory CD4 T cells (Mem) from EC display enhanced activity of the autophagy-mediated proteolysis compared to ART. Our results indicate that the enhanced autophagy activity in EC was controlled by the energy-sensing PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1). We further confirmed the critical role of the autophagy-mediated proteolysis in the strong IL21 production in EC by using gene silencing as well as protease, PRKAA1, and lysosomal inhibitors. Finally, we established that high autophagy-mediated proteolysis in EC fuels their cellular rates of mitochondrial respiration due to glutaminolysis. Our data confirm the critical role of autophagy in dictating the metabolic input, which is required not only to ensure protective cytotoxic CD8A T cell responses, but also to provide strong IL21 production among antiviral CD4 T cells. AKG: alpha-ketoglutarate; ART: patients under antiretroviral therapy; ATG7: autophagy related 7; BaF: bafilomycin A; BECN1: beclin 1; Chloro.: chloroquine; EC: elite controllers; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; FOXO3: forkhead box O3; GLS: glutaminase; GLUD1: glutamate dehydrogenase 1; HIV: HIV-1-uninfected control donors; IFNG/IFN-γ: interferon gamma; IL21: interleukin 21; MTOR: mechanistic target of rapamycin kinase; PBMC: peripheral blood mononuclear cells; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; SQSTM1: sequestosome 1; TCA: tricarboxylic acid cycle; ULK1: unc-51 like autophagy activating kinase.
记忆性 CD4 T 细胞中持续的 IL21 产生，尤其是在 HIV-1 特异性细胞中，是天然免疫保护免受该病毒侵害的主要相关因素。然而，在 HIV-1 感染期间导致 IL21 产生的分子机制仍不清楚，而这种产生仅在天然保护的精英控制者（EC）中升高。我们最近发现，脂噬作用是一种关键的免疫调节剂，它控制着 CD8A T 细胞受体结合后的抗病毒代谢状态，在 HIV-1 感染的自然控制中发挥着重要作用。这促使我们研究强大的巨自噬/自噬是否也可以用来确保有效的 IL21 产生。在此，我们证实，与接受抗逆转录病毒治疗（ART）的患者相比，EC 的记忆性 CD4 T 细胞（Mem）在多克隆和 HIV-1 特异性激活后表现出增强的自噬介导的蛋白水解活性。我们的结果表明，EC 中增强的自噬活性受到能量感应 PRKAA1（蛋白激酶 AMP 激活的催化亚基α1）的控制。我们通过使用基因沉默以及蛋白酶、PRKAA1 和溶酶体抑制剂进一步证实了自噬介导的蛋白水解在 EC 中强烈的 IL21 产生中的关键作用。最后，我们确定 EC 中的高自噬介导的蛋白水解作用通过谷氨酰胺分解作用为其细胞的线粒体呼吸提供燃料。我们的数据证实了自噬在决定代谢输入方面的关键作用，这不仅确保了保护性细胞毒性 CD8A T 细胞反应，而且还为抗病毒 CD4 T 细胞提供了强烈的 IL21 产生。AKG：α-酮戊二酸；ART：接受抗逆转录病毒治疗的患者；ATG7：自噬相关 7；巴氟霉素 A：Bafilomycin A；BECN1：自噬相关 10；氯喹：Chloroquine；EC：精英控制者；EIF4EBP1：真核翻译起始因子 4E 结合蛋白 1；FOXO3：叉头框 O3；GLS：谷氨酰胺酶；GLUD1：谷氨酸脱氢酶 1；HIV：HIV-1 未感染对照供体；IFNG/IFN-γ：干扰素 γ；IL21：白细胞介素 21；MTOR：雷帕霉素靶蛋白激酶；PBMC：外周血单核细胞；PRKAA1：蛋白激酶 AMP 激活的催化亚基α1；SQSTM1：自噬相关蛋白 1；TCA：三羧酸循环；ULK1：UNC-51 样自噬激活激酶。
