Lupus susceptibility gene Pbx1 regulates Treg metabolism 2603

Description The Sle1 lupus susceptibility locus contains the Pbx1 gene associated with disease susceptibility. The dominant-negative Pbx1 isoform, Pbx1-d, is overexpressed in lupus T cells, and it promotes Treg cell instability and defective suppressive functions. Since Pbx1 regulates cancer cell metabolism, this study aimed to determine whether Pbx1-d regulates Treg functions through metabolism. Here we showed that Pbx1-d overexpression in Jurkat T cells upregulates CamkIV, a glycolysis-driving gene over-expressed in lupus T cells and reduces Treg suppressive function. A luciferase assay established that the CamkIV promoter is a direct Pbx1-d transcriptional target relative to the normal Pbx1-b isoform. In addition, Pbx1-d overexpressing and Pbx1-deficient murine Treg cells exhibited significantly higher basal glycolysis and lower basal respiration to glycolysis ratio measured via Seahorse assays compared to WT, indicating that Pbx1-d overexpression or Pbx1 deletion drives Tregs towards a more glycolytic state, at least in part through CamkIV expression. Our results suggest that Pbx1-d may influence Treg homeostasis by shifting their metabolic program. Uncovering how Pbx1-d regulates Treg function may reveal ways to enhance Treg efficacy for adoptive therapies or address factors limiting their response in autoimmune conditions, advancing Treg-based treatments. Funding Sources R01 AI045050 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)