Low-dose fluoride exposure disrupts CD4⁺ T cell balance in humans and rats

This study aims to explore the effects of low-dose fluoride exposure (even within the World Health Organization safety limit: ≤1.5 mg/L) at different periods on CD4⁺ T cell-mediated adaptive immunity and its underlying mechanisms. In the human study, cytometry by time-of-flight (CyTOF) technology was used to establish the immune profiles of CD4⁺ T cells in individuals from low- and high-fluoride exposure areas for the first time. Cluster analysis revealed significant differences in the proportions of T helper (Th) 1, Th17, Naïve T, and follicular helper T cells between these groups. Pseudotime analysis indicated that while different concentrations of water fluoride did not significantly alter the differentiation trajectory of CD4⁺ T cells, they did affect the proportions of the differentiated subsets. Additionally, rat models of low-, medium-, and high-fluoride exposure under different conditions (short-term, long-term, and water improvement intervention) were used to analyze changes in Th1, Th2, and Th17 subsets and related cytokines expression. Short-term high-fluoride exposure increased Th1, Th2, and Th17 proportions. Prolonged exposure, even under medium-fluoride conditions, increased Th2 and Th17 proportions. Changes in Th1/Th2 and Th1/Th17 ratios can occur even under low-fluoride conditions during long-term exposure. While water improvement reversed medium- and high-fluoride induced ratio changes, its recovery effects on low-fluoride-induced ratio changes remained limited. Chronic fluoride exposure reduced Th1 cytokines [interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin (IL)-2] while increasing IL-12p70, and decreased both Th2 (IL-4, IL-10) and Th17 cytokines (IL-17A, IL-6). Fluoride may mediate the imbalance of Th1/Th2 and Th1/Th17 through its effects on the expression of IFN-γ, IL-2, and IL-12p70. In summary, long-term low-dose fluoride exposure impairs adaptive immunity by disrupting CD4⁺ T-cell distribution and function, particularly by altering key cytokines like IFN-γ, IL-2, and IL-12p70, leading to Th1/Th2 and Th1/Th17 imbalance. This persistent immune imbalance warrants attention for its long-term health implications.