Autophagy-dependent glutaminolysis drives superior IL21 production in HIV-1-specific CD4 T cells.

ABSTRACT

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 BECN1 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.Abbreviations AKG alpha-ketoglutarate; ART patients under antiretroviral therapy; ATG7 autophagy related 7; BaF bafilomycin A1; 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; HIVneg 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.