Fig. 7: Type I interferons modulate the metabolic fitness of CD8⁺ T cells in patients with SLE.

In HC, TCR signaling (signal 1) is essential for CD8⁺ T cell survival. In IFN-High SLE patients, persistent activation of the TCR (signal 1) and the type I IFNα pathways (signal 2) triggers mitochondrial changes via increasing NAD+ consumption in CD8⁺ T cells resulting in lower spare respiratory capacity (SRC) and thus decreased bioenergetic fitness. Upon increased energy demand such as in response to antigen challenge or stress, IFNα-stimulated CD8⁺ T cells are more prone to die, and this could perpetuate autoimmunity by increasing the autoantigen load. NAD+ supplementation with NMN restored the NAD+ pool, increased the mitochondrial respiration, decreased mROS, and improved cell viability upon TCR restimulation. Figure was created with BioRender.com.