HSP60 controls mitochondrial ATP generation for optimal virus-specific IL-21-producing CD4 and cytotoxic CD8 memory T cell responses

• Published in: Communications biology 2024-12, Vol.7 (1), p.1688-19, Article 1688
• Main Authors: Ghahari, Nazanin, Shegefti, Saina, Alaei, Mahsa, Amara, Amine, Telittchenko, Roman, Isnard, Stéphane, Routy, Jean-Pierre, Olagnier, David, van Grevenynghe, Julien
• Format: Article
• Language: English
• Subjects: 13/21; 13/31; 14/28; 631/250/1619/554/1775; 631/250/2152/1566/1618; Adenosine Triphosphate - metabolism; Antiviral agents; Autophagy; Biomedical and Life Sciences; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell activation; Chaperonin 60 - immunology; Chaperonin 60 - metabolism; Cytotoxicity; Enzymes; Fatty acids; HIV; HIV Infections - immunology; HIV Infections - metabolism; HIV Infections - virology; HIV-1 - immunology; Hsp60 protein; Human immunodeficiency virus; Humans; Immune response; Immunological memory; Interleukin 21; Interleukins - metabolism; Ketoglutaric acid; Life Sciences; Lymphocytes; Lymphocytes T; Male; Memory cells; Memory T Cells - immunology; Memory T Cells - metabolism; Mitochondria; Mitochondria - immunology; Mitochondria - metabolism; Mitochondrial Proteins; T cell receptors; Viruses
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-07326-8

We have shown that virus-specific CD4 and CD8 memory T cells (TM) induce autophagy after T cell receptor (TCR) engagement to provide free glutamine and fatty acids, including in people living with HIV-1 (PLWH). These nutrients fuel mitochondrial ATP generation through glutaminolysis and fatty acid oxidation (FAO) pathways, to fulfill the bioenergetic demands for optimal IL-21 and cytotoxic molecule production in CD4 and CD8 cells, respectively. Here, we expand our knowledge on how the metabolic events that occur in the mitochondria of virus-specific TM down-stream of the autophagy are regulated. We show that HSP60 chaperone positively regulates the protein levels for multiple glutaminolysis- and FAO-related enzymes, thereby actively fueling the levels of cellular alpha-ketoglutarate (αKG) and related mitochondrial ATP-dependent antiviral T cell immunity in both CD4 and CD8 TM. Finally, we provide a way to rescue defective ATP generation in mitochondria and dependent effector functions in virus-specific TM including anti-HIV-1 protective responses, when HSP60 expression is impaired after TCR engagement in patients, in the form of dimethyl 2-oxoglutarate (DMKG) supplementation. Antiviral immune function in both CD4 and CD8 memory T cells, which relies on effective ATP generation in mitochondria, involves the resident chaperone HSP60 by assisting the expression of multiples mitochondrial enzymes after cell activation