Accelerated cell cycle progression of human regulatory T cell-like cell line caused by continuous exposure to asbestos fibers

Abstract

Asbestos exposure causes malignant tumors such as lung cancer and malignant mesothelioma. Based on our hypothesis in which continuous exposure to asbestos of immune cells cause reduction of antitumor immunity, the decrease of natural killer cell killing activity with reduction of NKp46 activating receptor expression, inhibition of cytotoxic T cell clonal expansion, reduced CXCR3 chemokine receptor expression and production of interferon-γ production in CD4+ T cells were reported using cell line models, freshly isolated peripheral blood immune cells from health donors as well as asbestos exposed patients such as pleural plaque and mesothelioma. In addition to these findings, regulatory T cells (Treg) showed enhanced function through cell-cell contact and increased secretion of typical soluble factors, interleukin (IL)-10 and transforming growth factor (TGF)-β, in a cell line model using the MT-2 human polyclonal T cells and its sublines exposed continuously to asbestos fibers. Since these sublines showed a remarkable reduction of FoxO1 transcription factor, which regulates various cell cycle regulators in asbestos-exposed sublines, the cell cycle progression in these sublines was examined and compared with that of the original MT-2 cells. Results showed that cyclin D1 expression was markedly enhanced, and various cyclin-dependent kinase-inhibitors were reduced with increased S phases in the sublines. Furthermore, the increase of cyclin D1 expression was regulated by FoxO1. The overall findings indicate that antitumor immunity in asbestos-exposed individuals may be reduced in Treg through changes in the function and volume of Treg.

Aberrant expression of FoxP3 in a human T�cell line possessing regulatory T cell‑like function and exposed continuously to asbestos fibers

“…FoxO1 acts by regulating cell cycle-related genes, with negative regulation for accelerating cyclins and positive regulation for breaking cyclin-dependent kinase-inhibitors (CDK-Is). Thus, all sublines showed increased expression of cyclins and decreased expression of CDK-Is which resulted in the acceleration of cell cycle progression (31). These findings indicate that asbestos exposure induces enhanced Treg function as well as proliferation.…”

Immune Alteration Caused by Fibrous and Particulate Environmental Substances

“…In addition, in cell cycle phase analysis, subline showed higher S/G1 ratio (S-phase% was divided with G1 phase%) than that of original line. In addition, knockdown of FoxO1 in subline using siRNA induced increased expression of cyclin D1, the most enhanced expression in subline [54]. These results indicated that reduced FoxO1 caused by asbestos exposure induced enhancement of cell cycle progression.…”

414 Induction of il-17 production from human peripheral blood cd4+ cells by asbestos exposure

“…For example, as previously reported, continuous exposure of the human NK cell line YT-A1 to chrysotile asbestos for more than five months resulted in reduced antitumor killing activity against the human erythroblastic leukemia cell line K562, a commonly used target cell line to assay NK cell activity and compared with the original YT-A1 cell line, which has never been exposed to asbestos fibers (7-9). Regarding our previous reports showing that asbestos fibers enhance Treg function (43) and increase its volume by acceleration of the cell cycle (44), the construction of a cell co-culture model using human cell lines such as a Treg cell model or responder T cell model with mesothelioma (or other cancer) model might be difficult. As we previously reported, subjecting a human Treg model comprising the MT-2 cell line to continuous exposure to asbestos resulted in increased production of IL-10 and TGFβ (43).…”