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B and Expression of Fas Ligand in Thymic Stromal Cells and Consequent Apoptosis in T Cells1
Departments of*
Microbiology and Immunology and Pharmacology and Toxicology, Virginia Commonwealth University Medical Center, Richmond, VA 23298
We investigated the role of aryl hydrocarbon receptor (AhR) in the regulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced apoptosis in thymic T cells. AhR knockout (KO) mice were resistant to TCDD-induced thymic atrophy and apoptosis when compared with the AhR wild-type mice. TCDD triggered the expression of several apoptotic genes, including FasL in AhR wild-type but not AhRKO mice. TCDD-induced increase in FasL was seen only in thymic stromal but not thymic T cells. When TCDD-exposed stromal cells were mixed with untreated thymic T cells, increased apoptosis was detected in T cells that involved Fas-FasL interactions. Thus, apoptosis in T cells was not detected when TCDD-treated stromal cells from FasL-defective or AhRKO mice were mixed with wild-type T cells or when TCDD-exposed wild-type stromal cells were mixed with Fas-deficient T cells. TCDD treatment, in vivo and in vitro, led to colocalization and translocation of NF-
B subunits (p50, p65) to the nucleus in stromal but not T cells from AhR wild-type mice. NF-B activation was not observed in stromal cells isolated from TCDD-treated AhRKO mice. Mutations in NF-B-binding sites on the FasL promoter showed that TCDD regulates FasL promoter activity through NF-B. TCDD treatment in vivo caused activation of the death receptor and mitochondrial pathways of apoptosis. Cross-talk between the two pathways was not necessary for apoptosis inasmuch as TCDD-treated Bid KO mice showed thymic atrophy and increased apoptosis, similar to the wild-type mice. These findings demonstrate that AhR regulates FasL and NF-B in stromal cells, which in turn plays a critical role in initiating apoptosis in thymic T cells.
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