Excess T3 is associated with regulatory B-cell dysfunction and HDAC3-related autophagy changes in graves' disease

Graves' disease (GD) is characterized by immune dysregulation, but whether the hyperthyroid endocrine environment contributes to impaired immune tolerance remains unclear. We examined IL-10-producing B10/B10pro-enriched regulatory B cells and the involvement of autophagy-related regulation, thyroid hormone receptor (TR) signaling, and HDAC3. Patients with Graves' hyperthyroidism showed reduced Breg frequency and IL-10-producing capacity with altered LC3/p62 profiles. In vitro, high T3 reduced autophagic flux, IL-10 output, and Lpcat1/Rab22a expression. Combined THRA/THRB knockdown or TR antagonism attenuated the reductions in Lpcat1/Rab22a expression and IL-10 output, whereas the TRβ-selective agonist GC-1 produced changes in the same direction. Lpcat1 or Rab22a overexpression partially restored IL-10 secretion and reduced T-cell inflammatory readouts under high T3. HDAC3 loss-of-function in IM-9 cells partially restored Lpcat1/Rab22a expression, autophagy-related markers, and IL-10. Endpoint ChIP-PCR across a T3 concentration series showed T3-associated TRβ/HDAC3/NCoR signal changes with reciprocal H3K27ac changes at candidate promoter regions evaluated in a motif-guided scan. Together, the findings support a TR-dependent, HDAC3-associated working model in which excessive T3 may contribute to regulatory B-cell dysfunction through changes in Lpcat1/Rab22a expression and autophagy-related processes.