Formaldehyde exposure induces regulatory T cell-mediated immunosuppression via calcineurin-NFAT signalling pathway

Abstract

In this study, we investigated the effects of Formaldehyde (FA) exposure on splenic immune responses wherein helper T cells become activated and differentiate into effector T and regulatory T cells. BALB/c mice were exposed to two FA concentrations (1.38 mg/m3 and 5.36 mg/m3) for 4 h/day and 5 days/week for 2 weeks. FA-induced immune responses were examined by the production of cytokines, expression of mRNAs, and distributions of helper T cells and regulatory T cells. Moreover, expression of calcineurin and NFATs, regulatory T cell-related signalling proteins, were evaluated. FA exposure suppressed Th2-, Th1-, and Th17-related splenic cytokines in a dose-dependent manner. mRNA expression of splenic cytokines was also decreased by FA exposure, which correlated with decreased cytokine expression. In parallel, FA exposure promoted T cell differentiation into regulatory T cells in a dose-dependent manner supported by the expression of calcineurin and NFAT1. Taken together, our results indicated that FA exposure increases the number of regulatory T cells via calcineurin-NFAT signalling, thereby leading to effector T cell activity suppression with decreased T cell-related cytokine secretion and mRNA expression. These findings provide insight into the mechanisms underlying the adverse effects of FA and accordingly have general implications for human health, particularly in occupational settings.

Formaldehyde exposure induces differentiation of regulatory T cells via the NFAT-mediated T cell receptor signalling pathway in Yucatan minipigs

“…Our results demonstrate that FA exposure suppressed the expression of all helper T cell-related genes in a concentration-dependent manner, while IL-4 expression was significantly decreased at all inhaled concentrations. These findings are consistent with the results of our previous study, which showed the suppression of Th-1, Th-2, and Th-17 cell-related splenic cytokine production and mRNA expression due to FA exposure in a concentration-dependent manner 46 . Furthermore, Wei et al reported that levels of helper T cell-related cytokines were suppressed in FA-exposed C57BL/6 mice 29 .…”

“…No significant differences were observed between the total and differential cell counts of the FA-exposed and control groups. These findings are consistent with those of previous studies showing that exposure to FA does not induce significant differences in the counts of various inflammatory cell types in bronchoalveolar lavage fluid 30 , 46 . However, in the histopathological analysis, infiltration of inflammatory cells and degeneration of the bronchial epithelium were noted to be increased in the 10.48 mg/m 3 FA exposure group.…”

“…However, exposure to FA significantly increased the population size of splenic CD4 + Foxp3 + Treg cells. Thus, our findings are consistent with those of prior studies on FA-exposed human and rodent models 32 , 46 , 59 , 60 .…”

“…Other studies have also shown that FA exposure affects immune responses, including helper T cells and lung inflammation-related up- and down-regulation of gene and protein expression 32 , 51 , 52 . Additionally, the mouse FA concentrations used in several studies were converted into minipig FA concentrations using Alexander's formula 53 ; these results and the common ratio of 2 are reflected in our exposure concentrations (Park et al 46 : 1.38, 5.36 mg/m 3 → 0.84, 3.27 mg/m 3 ; Tarkowski et al 54 : 2 mg/m 3 → 1.83 mg/m 3 ; Liu et al 28 : 0.5, 3 mg/m 3 → 0.96, 5.77 mg/m 3 ; Li et al 27 : 0.5, 3 mg/m 3 → 1.14, 6.86 mg/m 3 ; Jung et al 32 and Kim et al 50 ; 5, 10 ppm → 5.64, 11.38 mg/m 3 ). Thus, based on these studies and their results, we exposed minipigs to 2.16, 4.62, and 10.48 mg/m 3 at 2 h/day for 2 weeks (5 days a week).…”

“…In the spleen, the proper differentiation and development of different subsets of effector T cells (Th1, Th2) and Treg cells are initiated in the presence of lineage-specific effector cytokines during T cell activation 56 . Recent human and animal studies have reported that FA exposure adversely affects the immune system by altering the population of different types of T cells as well as the production of helper T cell-related cytokines 29 , 33 – 35 , 46 . Thus, we investigated the potential effect of FA exposure on splenic immune responses by evaluating the expression of helper T cell-related mRNAs and cytokines in splenocytes that were activated by Concanavalin A, which induces the mitogenic activity of T cells and increases the synthesis of cellular products.…”