Cytoplasmic NAD/H synthesis via NRK1 regulates inflammatory capacity and promotes survival of CD4+ T cells

Stavrou, V, Ali, M, Gudgeon, N, Bishop, EL, Fulton-Ward, T, Turley, B, Heising, S, Mohamed, SH, Hain, S, George, L, Deng, M, McCowan, J, Sheriff, L, Davies, SP, Marzullo, B, Tennant, DA, Doig, CL ORCID: https://orcid.org/0000-0001-9694-4230, Bending, DA, Roberts, EW, Lavery, GG ORCID: https://orcid.org/0000-0001-5794-748X, Drummond, RA and Dimeloe, S, 2026. Cytoplasmic NAD/H synthesis via NRK1 regulates inflammatory capacity and promotes survival of CD4+ T cells. Nature Communications. ISSN 2041-1723

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Abstract

T cell metabolism increases upon activation, underpinning immune effector functions. Nicotinamide adenine dinucleotide (NAD/H) is an essential redox cofactor for glycolysis and mitochondrial substrate oxidation. It’s phosphorylation to NADP/H regulates reactive oxygen species (ROS) abundance. NAD/H levels increase upon T cell activation, but synthesis pathways and implications are not fully characterised. Here, we interrogate the role of the NAD/H-synthesis enzyme nicotinamide riboside kinase 1 (NRK1), the expression of which increases upon stimulation of both human and murine CD4+ T cells. Functionally, NRK1 activity restrains activation and cytokine production of CD4+ T cells while promoting survival. These activities are linked to increased NRK1 expression in the cytoplasm, where it locally raises NAD/H levels. This supports glycolysis, but more profoundly impacts cytoplasmic NADP/H generation, thereby controlling ROS abundance and nuclear NFAT translocation. During fungal and viral infection, T-cell-intrinsic NRK1 maintains effector CD4+ T cell abundance within affected tissues and draining lymph nodes, supporting infection control. Taken together, these data confirm that subcellular regulation of immune cell metabolism determines immune responses at the level of whole organism.

Item Type:	Journal article
Publication Title:	Nature Communications
Creators:	Stavrou, V., Ali, M., Gudgeon, N., Bishop, E.L., Fulton-Ward, T., Turley, B., Heising, S., Mohamed, S.H., Hain, S., George, L., Deng, M., McCowan, J., Sheriff, L., Davies, S.P., Marzullo, B., Tennant, D.A., Doig, C.L., Bending, D.A., Roberts, E.W., Lavery, G.G., Drummond, R.A. and Dimeloe, S.
Publisher:	Springer
Date:	4 February 2026
ISSN:	2041-1723
Identifiers:	Number Type 10.1038/s41467-026-68863-w DOI 2572698 Other
Rights:	This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	11 Feb 2026 17:48
Last Modified:	11 Feb 2026 17:48
URI:	https://irep.ntu.ac.uk/id/eprint/55230

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