Regulatory T Cells and IFNγ in Mercury-Induced Autoimmunity: Insights from Adoptive Transfer in B10.S Mice

Autoimmune diseases result from a breakdown of immune tolerance influenced by genetic and environmental factors. Regulatory T cells (Tregs) maintain immune homeostasis, while interferon-γ (IFNγ) has context-dependent proinflammatory and regulatory roles. In B10.S mice, mercury-induced autoimmunity (HgIA) emerges within approximately 4 weeks of Hg exposure and is marked by antinucleolar antibody (ANoA) production, polyclonal B-cell activation, and deposition of immune complexes in the kidney. We investigated whether Tregs attenuate HgIA and evaluated IFNγ’s role in this regulation. Female WT and IFNγ−/− B10.S mice received HgCl2 or water for 4 weeks until all mice developed ANoA. CD4+CD25+Foxp3+ Tregs or CD4+CD25−Foxp3− cells were transferred into HgCl2-exposed WT recipients and monitored for 13 weeks. Compared with Hg-primed non-Tregs, Hg-primed WT Tregs were statistically associated with significantly reduced autoantibody levels, lower IgG1/IgG2a, and significantly decreased glomerular IgG/C3c deposition, suggesting that Hg exposure may modulate Treg function. Conversely, both water- and Hg-primed Tregs and non-Tregs from IFNγ−/− donors elicited profoundly diminished autoantibody production and renal pathology in recipients. IFNγ−/− mice lacked fibrillarin-specific responses, highlighting its requirement for HgIA initiation. While non-Treg transfer failed to suppress HgIA, Treg transfer reduced HgIA and highlighted relevance for immune-regulatory therapies, especially where environmental toxicants may drive autoimmune disease.