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

Interferon y (IFNy) 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 IFNy 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 IFNy 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 IFNy 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 IFNy-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.