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

## TL;DR

Regulatory T cells can reduce mercury-induced autoimmune damage, but they need IFNγ to function properly.

## Contribution

The study reveals that IFNγ is essential for Tregs to suppress mercury-induced autoimmunity in mice.

## Key findings

- Tregs from mercury-exposed mice reduced harmful antibodies and kidney injury in recipients.
- Tregs from IFNγ-deficient mice were less effective and failed to suppress autoimmunity.
- IFNγ is required for the initiation of mercury-induced autoimmune responses.

## Abstract

Autoimmune diseases occur when the immune system mistakenly attacks the body’s own tissues. This can happen due to a mix of genetic and environmental factors. Special immune cells called regulatory T cells (Tregs) normally keep the immune system in balance, while a molecule called interferon-gamma (IFNγ) can both promote and regulate inflammation depending on the situation. In the present study, we studied mercury-induced autoimmunity (HgIA) in mice, a condition triggered by mercury exposure that causes harmful antibodies and kidney damage. We tested whether Tregs could reduce this disease and whether IFN-γ was important for their function. When Tregs from mercury-exposed mice were transferred to other mice, they greatly reduced harmful antibodies and kidney injury. However, Tregs from mice lacking IFNγ were much less effective, and those mice still developed signs of autoimmunity. The study shows that Tregs can protect against mercury-related autoimmune damage, but they need IFNγ to work properly. This highlights IFNγ as a key partner for Tregs in controlling harmful immune responses during chronic exposure to environmental toxins like mercury.

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.