Reductive Alteration of the Regulatory Function of the CD4+CD25+ T Cell Fraction in Silicosis Patients

Abstract

Causal links have been documented between silica and rheumatoid arthritis, lupus erythematosus, systemic sclerosis and glomerulonephritis. Two different effects of silica have been suggested, an enhanced inflammatory response in the pulmonary region (e.g. activation of alveolar macrophages) and dysregulation of autoimmunity. Based on our previous reports showing in vitro activation of peripheral T cells by silica and reduced regulatory function of the peripheral CD4⁺CD25⁺ fraction in which FoxP3⁺ regulatory T cells (Treg) are located, reconstitution of the CD4⁺CD25⁺ fraction in silicosis patients (SILs) was investigated. Since T cells in peripheral CD4⁺CD25⁺ and CD4⁺CD25⁻ (effector T cells; Teff) fractions from SILs showed higher expression of pd-1 (a marker gene for T cell activation) in comparison to that of healthy donors (HDs), chronic T cell activation was considered to have occurred in SILs. In this study, a higher expression of the CD95/Fas molecule in Treg was recorded from silicosis patients (SILs) compared to healthy donors (HDs), and excess loss of FoxP3⁺ Treg in freshly isolated peripheral blood mononuclear cells (PBMCs) from SILs relative to HDs was demonstrated when these cells were cultured with silica ex vivo, whereas CD25⁺ cells were not reduced due to contamination of activated Teff in the CD4⁺CD25⁺ fraction. The activation of both Teff and Treg results in reconstitution of the peripheral CD4⁺ CD25⁺ fraction, loss of Treg and contamination of activated Teff, resulting in reduction of the number and function of Treg. These results contribute to our understanding of the development of autoimmune diseases found in SILs.