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

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Overview

This mechanistic mouse study investigated the roles of regulatory T cells (Tregs) and interferon-gamma (IFNgamma) in mercury-induced autoimmunity (HgIA) using the B10.S mouse model, which recapitulates features of systemic autoimmune disease including antinucleolar antibody (ANoA) production, polyclonal B-cell activation (PBA), and glomerular immune-complex (IC) deposition. Tregs and non-Tregs from water-primed or mercury-primed wild-type (WT) or IFNgamma-knockout (IFNgamma-/-) B10.S mice were adoptively transferred into WT recipient mice subsequently exposed to mercury for 13 weeks. The core finding is that Tregs from mercury-primed donors markedly suppressed ANoA production, B-cell activation, and renal IC deposition, while Tregs from IFNgamma-deficient donors showed minimal suppressive efficacy, identifying IFNgamma as a critical cofactor for effective Treg-mediated protection against mercury-driven autoimmunity.

Key numbers

  • Donor exposure: 4 mg HgCl2/L in drinking water for 4 weeks (corresponding to a LOAEL of 0.23 to 0.63 mg/kg body weight per day, referenced to WHO guidance). All recipient mice exposed to 4 mg HgCl2/L for 13 weeks post-transfer.
  • Group C (recipients of non-Treg cells from mercury-primed donors): total IgG ANoA titer rose to 2690 +/- 510 at week 13; all mice (100%) positive.
  • Group D (recipients of Treg cells from mercury-primed donors): total IgG ANoA titer fell to 20 +/- 20 at week 13; only 30% positive (statistically significant difference from group C, p ⇐ 0.001).
  • Group B (recipients of Treg cells from water-primed donors): ANoA peaked at 220 at week 5 and declined to 190 at week 13; 60% positive — partial suppression compared with 100% in group A (non-Treg, water-primed).
  • IFNgamma-/- donor groups (E-H): uniformly muted autoimmune phenotype regardless of T-cell type; ANoA essentially absent; glomerular IC deposition not significantly elevated. This demonstrates IFNgamma dependence of the autoimmune response itself.
  • Glomerular IC deposition: Tregs from mercury-primed donors (group D) showed markedly reduced C3c and IgG renal deposits compared with non-Treg recipients (group C; p <0.001).
  • Anti-fibrillarin response: Treg-recipient mice showed no reactivity to the 34 kDa fibrillarin protein on western blot; non-Treg recipients showed clear fibrillarin reactivity (IgG ANoA titer 1:320 or higher).
  • IgG2a-IgG1 ANoA index: Tregs consistently showed lower IgG2a-predominant index values (Th2-associated IgG1 responses), while non-Tregs showed higher IgG2a (Th1-associated) responses.

Methods (brief)

Adoptive T-cell transfer experiment in B10.S inbred mice (H-2s). Female WT B10.S and IFNgamma-/- (B10.S IFNgamma-/-) mice used as donors (n=20 each genotype). Tregs isolated as CD4+CD25+Foxp3+ cells; non-Tregs as CD4+CD25- cells; purity assessed by magnetic separation and flow cytometry. Approximately 1x10^6 cells transferred intravenously per recipient. All recipients exposed to 4 mg HgCl2/L in drinking water for 13 weeks. Blood sampled at weeks 5, 7, 9, and 13. ANoA by indirect immunofluorescence on HEp-2 cells. Anti-chromatin, anti-DNP, and anti-ssDNA by ELISA. Serum IgG1 and IgG2a by ELISA. Glomerular IC (IgG and C3c) by direct immunofluorescence on kidney sections. Statistical analysis: Kruskal-Wallis followed by Dunn’s post hoc; Mann-Whitney pairwise comparisons. Animal ethics approved (ethical # 62-07, Linkoping).

Limitations

Study uses an inbred mouse model (B10.S) genetically susceptible to mercury autoimmunity; findings may not generalize across genetic backgrounds. Mechanistic interpretations (epigenetic Treg priming, IFNgamma-dependent B-cell switch) are speculative hypotheses the authors flag as requiring further experimental confirmation. Lack of detailed IFNgamma-/- Treg phenotypic characterization limits lineage interpretation. The IFNgamma requirement for the autoimmune response itself (not only for Treg function) is a confounding factor in interpreting the IFNgamma-/- Treg transfer results.

Implications

Certification: Establishes IFNgamma and Treg function as mechanistic checkpoints in mercury-induced systemic autoimmunity. Relevant to HMT&C’s mercury (tHg, MeHg) rationale for protecting against autoimmune and renal outcomes.

Courses: Core mechanistic reference for the autoimmunity and mercury module. Illustrates Treg-based immune regulation and the dual role of IFNgamma in both driving and restraining autoimmune pathology.

App: No food concentration data. Mechanistic context for mercury-autoimmunity endpoint.

Microbiome: Does not address gut microbiota directly; Treg/IFNgamma axis has gut-immune implications that could be linked in a WikiBiome entry on mercury and immune regulation.

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