NAMPT is a metabolic checkpoint of IFNγ-producing CD4+ T cells in lupus nephritis

Abstract

Interferon γ (IFNγ) produced by T cells represents the featured cytokine and is central to the pathogenesis of lupus nephritis (LN). Here, we identified nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage NAD⁺ biosynthetic pathway, as playing a key role in controlling IFNγ production by CD4⁺ T cells in LN. Our data revealed that CD4⁺ T cells from LN showed an enhanced NAMPT-mediated NAD⁺ biosynthetic process, which was positively correlated with IFNγ production in CD4⁺ T cells. NAMPT promoted aerobic glycolysis and mitochondrial respiration in CD4⁺ T cells from patients with LN or MRL/lpr mice through the production of NAD⁺. By orchestrating metabolic fitness, NAMPT promoted translational efficiency of Ifng in CD4⁺ T cells. In vivo, knockdown of NAMPT by small interfering RNA (siRNA) or pharmacological inhibition of NAMPT by FK866 suppressed IFNγ production in CD4⁺ T cells, leading to reduced inflammatory infiltrates and ameliorated kidney damage in lupus mice. Taken together, this study uncovers a metabolic checkpoint of IFNγ-producing CD4⁺ T cells in LN in which therapeutically targeting NAMPT has the potential to normalize metabolic competence and blunt pathogenicity of CD4⁺ T cells in LN.

Keywords: IFNγ expression; NAMPT; lupus nephritis; metabolic checkpoint; translation efficiency.