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

Ghahari, Nazanin; Shegefti, Saina; Alaei, Mahsa; Amara, Amine; Telittchenko, Roman; Isnard, Stephane; Routy, Jean-Pierre; Olagnier, David et van Grevenynghe, Julien ORCID: https://orcid.org/0000-0002-2952-4081 (2024). HSP60 controls mitochondrial ATP generation for optimal virus-specific IL-21-producing CD4 and cytotoxic CD8 memory T cell responses Communications Biology , vol. 7 , nº 1688. pp. 1-19. DOI: 10.1038/s42003-024-07326-8.

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Résumé

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.

Type de document:	Article
Mots-clés libres:	-
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	06 janv. 2025 06:02
Dernière modification:	06 janv. 2025 06:02
URI:	https://espace.inrs.ca/id/eprint/16244

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