Exposure to a metabolite of the environmental toxicant, trichloroethylene, attenuates CD4+ T cell activation-induced cell death by metalloproteinase-dependent FasL shedding

Long-term exposure to the environmental contaminant trichloroethylene (TCE) in drinking water has been shown to promote autoimmune disease in association with the expansion of activated CD4(+) T cells. The effects of TCE on CD4(+) T cells were linked in the present study to the ability of TCE metabolite, trichloroacetaldehyde hydrate (TCAH), to inhibit activation-induced cell death (AICD) in CD4(+) T cells. TCAH attenuated AICD in CD4(+) T cells by decreasing Fast, (CD178) expression but not by altering Fas (CD95) expression or by interfering with Fas-signaling events following direct engagement of the Fas receptor. The TCAH-induced decrease in Fast, expression did not appear to be mediated at the transcriptional level but was instead due to increased shedding of Fast, from the surface of the CD4(+) T cells. The ability of TCAH to cleave Fast, and thereby decrease AICD appeared to be mediated by metalloproteinases and correlated with a TCAH-induced increase in matrix metalloproteinase-7. Thus, this study presents the novel finding that the environmental contaminant TCE works via its metabolite TCAH to attenuate AICD by increasing metalloproteinase activity that cleaves Fast, from CD4(+) T cells. This represents a mechanism by which an environmental trigger inhibits AICD in CD4(+) T cells and may thereby promote CD4(+) T cell-mediated autoimmune disease.