Autoimmune Disease Risk Gene ANKRD55 Promotes Th17 Effector Function Through Metabolic Modulation [ATAC-Seq]

Genome-wide association studies (GWAS) have linked the locus encoding Ankyrin Repeat Domain 55 (ANKRD55) with numerous autoimmune diseases; however, its biological function and role in inflammation are unclear. Here, we demonstrate that Ankrd55-deficient mice are protected from T cell-mediated colitis but are more susceptible to Citrobacter rodentium infection. Mechanistically, Ankrd55 deletion impairs CD4+ T cell proliferation and reduces effector cytokine production in T helper 17 (TH17) cells in a cell-intrinsic manner. ANKRD55 is associated with mitochondria, and its loss is associated with impaired mitochondrial respiration and activation of the LKB1 pathway. Consistently, IL-17 production can be rescued by the deletion of LKB1 in Ankrd55-deficient T cells. Altogether, our study implicates the protein ANKRD55 as a functional modulator of T cell metabolism that directly impacts TH17 responses, highlighting it as a potential target across multiple autoimmune diseases. T cells were harvested from wild-type or Ankrd55-deficient animals and differentiated in vitro towards different helper phenotypes. Bulk ATAC sequencing was performed at the end of the differentiation process.