Thymocyte development in Ah-receptor-deficient mice is refractory to TCDD-inducible changes

The arylhydrocarbon receptor (AhR), a ligand-activated transcription factor , is differentially distributed in tissues and abundant in the thymus epith elium. The activated AhR can induce the transcription of an array of genes, including genes of cell growth and differentiation. Neither the physiologi cal function of the AhR nor its putative natural ligand is known. 2,3,7,8-t etrachlorodibenzo-p-dioxin (TCDD) is a xenobiotic high-affinity activator o f the AhR, and appears to be essential for most of the multifold toxic effe cts of TCDD. Activation of the AhR by even low doses of TCDD results in gen eral immunosuppression and thymus hypoplasia. TCDD exposure interferes with thymocyte development; for instance, it reduces the proliferation rate of the very immature (CD4(-)CD8(-) and CD4(-)CD8(+)HSA(+)) thymocytes, leads t o preferential emigration of very immature cells, and drastically skews the differentiation of thymocyte subpopulations towards mature CD4(-)CD8(+) al pha beta TCRhigh thymocytes. As shown here, in fetal thymi of AhR-deficient mice, thymocyte differentiation kinetics as defined by CD4 and CD8 surface markers, was comparable to AhR(+/+) C57BL/6 mice. Also, the cell emigratio n characteristics were similar to AhR(+/+) mice. These parameters were refr actory to TCDD exposure in the AhR(-/-) mice, but not in the C57BL/6 mice. However, in AhR deficient mice at gestation day 15 more CD4(-)CD8(-) immatu re cells bore high amounts of the (alpha beta-T-cell receptor. Also, fetal thymocyte numbers were significantly lower, as compared to strain C57BL/6. Thus, the AhR is the mediator of thymotoxic effects of TCDD. Published by E lsevier Science Ltd. All rights reserved.