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

## TL;DR

This study shows that the enzyme NRK1 helps CD4+ T cells survive and control infections by regulating NAD/H and reactive oxygen species in the cytoplasm.

## Contribution

The study identifies NRK1 as a key regulator of CD4+ T cell metabolism and survival during immune responses.

## Key findings

- NRK1 expression increases in CD4+ T cells upon activation in both mice and humans.
- NRK1 promotes T cell survival while restraining cytokine production and activation.
- NRK1 regulates NADP/H and ROS signaling, impacting NFAT translocation and infection control.

## 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.

T cell activation requires major metabolic adaptation. Here authors find that in mice and humans, expression of the NAD/H-synthesis enzyme nicotinamide riboside kinase 1 (NRK1) increases in CD4+ T cells upon activation, particularly within the cytoplasm, which impacts NADP/H and reactive oxygen species signalling, restraining activation and cytokine production while promoting CD4 + T cell survival during viral and fungal infections.