{
  "abstract": "Objectives Aberrant T cell responses are known to contribute to SLE pathogenesis. Mitochondrial oxidative phosphorylation (OXPHOS) supports pathogenic activation and oxidative stress, and type I interferons (IFN-I) can reprogramme lymphocyte bioenergetics. Whether IFN-I further skews CD4+ T cell metabolism in SLE is unclear. We sought to determine if SLE CD4+ T cells display altered mitochondrial content and function, and whether IFN-alpha modulates these pathways.Methods Patients with well controlled SLE (n=33, median SLEDAI-2K=2) and healthy controls (HC, n=17) were recruited. Flow cytometry quantified mitochondrial mass (MitoTracker) in CD4+ and CD8+ T cells including naïve (CD45ro-CCR7+), central memory (CM, CD45ro+CCR7+), TEMRA (CD45ro-CCR7-) and effector memory (EM, CD45ro+CCR7-) subsets. CD4+ T cells were negatively enriched from PBMCs and profiled using Seahorse XF MitoStress to measure OXPHOS via oxygen consumption rate (OCR) and glycolysis via extracellular acidification rate (ECAR). To assess IFN-I effects, matched CD4+ T cells from SLE and HC were cultured ± recombinant human IFN-alpha (1,000 U/mL, 16 h) prior to Seahorse testing.Results SLE CD4+ T cells displayed higher mitochondrial mass than HC across naïve, CM, EM, and TEMRA-like subsets ( figure 1A). CD8+ T cells showed subset-specific reductions (figure 1B). Ex vivo SLE CD4+ T cells had elevated basal and maximal OXPHOS (figure 1C–D), and increased basal and maximal glycolysis (figure 1E–F). Despite higher respiration, spare respiratory capacity was unchanged (figure 1G), while proton leak was increased (figure 1H), uncoupling efficiency reduced (figure 1I), and ATP production higher (figure 1J), indicating a hypermetabolic yet energetically inefficient state with mitochondrial stress. IFN-alpha had minimal effect on basal OXPHOS in HC and reduced glycolytic flux, consistent with context-dependent restraint. In SLE CD4+ T cells, IFN-alpha further increased basal OXPHOS without altering maximal capacity (figure 1K–L) and raised basal glycolysis with unchanged maximal ECAR (figure 1M–N), amplifying baseline bioenergetic demand.Abstract PT1:02 Figure 1Conclusions SLE CD4+ T cells exhibit mitochondrial expansion and a hypermetabolic profile. IFN-alpha selectively augments basal respiratory and glycolytic flux, implicating IFN-I in sustaining pathogenic T cell metabolism. These data support a model in which IFN-driven metabolic reprogramming of CD4+ T cells contribute to SLE pathogenesis and highlight bioenergetic checkpoints as rational targets for immunometabolic intervention.",
  "authors": [
    {
      "affiliations": [
        "King’s College Hospital, London, UK"
      ],
      "name": "Chris Wincup"
    },
    {
      "affiliations": [
        "UCL Great Ormond Street Institute of Child Health, London, UK"
      ],
      "name": "Meredyth Wilkinson"
    },
    {
      "affiliations": [
        "University College London, London, UK"
      ],
      "name": "George Robinson"
    },
    {
      "affiliations": [
        "University College London, London, UK"
      ],
      "name": "Anisur Rahman"
    }
  ],
  "title": "PT1:02 Mitochondrial expansion and interferon-driven bioenergetic reprogramming define CD4+ T cell dysfunction in systemic lupus erythematosus",
  "uid": "efa5ca70-8e4f-5515-b177-362601feab98"
}