Nicotinamide breaks effector CD8 T cell responses by targeting mTOR signaling

Federica Agliano; Timofey A Karginov; Antoine Ménoret; Anthony Provatas; Anthony T Vella

doi:10.1016/j.isci.2022.103932

Nicotinamide breaks effector CD8 T cell responses by targeting mTOR signaling

iScience. 2022 Feb 15;25(3):103932. doi: 10.1016/j.isci.2022.103932. eCollection 2022 Mar 18.

Authors

Federica Agliano¹, Timofey A Karginov¹, Antoine Ménoret¹, Anthony Provatas², Anthony T Vella¹

Affiliations

¹ Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030 USA.
² Department of Chemistry, University of Connecticut, Storrs, CT 06269 USA.

Abstract

Nicotinamide (NAM) shapes T cell responses but its precise molecular mechanism of action remains elusive. Here, we show that NAM impairs naive T cell effector transition but also effector T cells themselves. Although aerobic glycolysis is a hallmark of activated T cells, CD8⁺ T cells exposed to NAM displayed enhanced glycolysis, yet producing significantly less IFNγ. Mechanistically, NAM reduced mTORC1 activity independently of NAD⁺ metabolism, decreasing IFNγ translation and regulating T cell transcriptional factors critical to effector/memory fate. Finally, the role of NAM in a biomedically relevant model of lung injury was tested. Specifically, a NAM-supplemented diet reduced systemic IL-2, antigen-specific T cell clonal expansion, and effector function after inhalation of Staphylococcus aureus enterotoxin A. These findings identify NAM as a potential therapeutic supplement that uncouples glycolysis from effector cytokine production and may be a powerful treatment for diseases associated with T cell hyperactivation.

Keywords: Biological sciences; Immunology; Molecular biology.