Generation of αβ T‐cell receptor+ CD4– CD8+ cells in major histocompatibility complex class I‐deficient mice upon activation of the aryl hydrocarbon receptor by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin

• Published in: Immunology 2000-06, Vol.100 (2), p.185-193
• Main Authors: Kronenberg, S., Lai, Z.‐W., Esser, C.
• Format: Article
• Language: English
• Subjects: Original
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1046/j.1365-2567.2000.00022.x

Gene-targeted mice lacking the β 2 microglobulin gene (β 2 m −/− mice), and hence functional major histocompatibility complex (MHC) class I molecules, do not develop CD4 – CD8 + cells. We show here that both in vitro and in vivo treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a trans-activating ligand of the endogenous aryl hydrocarbon receptor (Ah-R), bypasses the need for MHC class I molecules for selection into the CD4 – CD8 + cell pool. When β 2 m −/− dams were given a single dose of 50 mg of TCDD, ≈ 13% of CD4 – CD8 + thymocytes could be detected in their newborn pups. In TCDD-exposed fetal thymus organ cultures of β 2 m −/− mice, ≈ 35% CD4 – CD8 + thymocytes were detectable. About 16% of these CD4 – CD8 + cells bore the ab T-cell receptor (TCR) and ≈ 33% bore CD3. Only a minority of the CD8 + cells were heat-shock antigen positive. The cells possessed killing activity as shown using the 51Cr-release assay comprising cd TCR± CD4 – CD8 + thymocytes from 3 to 4-day-old β 2 m −/− mice. Thus, TCDD leads to a signi®cant increase of mature CD4 – CD8 + thymocytes in relative and absolute numbers. High numbers of CD4 – CD8 + thymocytes developed also in organ cultures from thymi, lacking both MHC class I and class II molecules, exposed to TCDD. A 10-fold transient increase of Notch1 mRNA in thymocytes from fetal thymus organ culture, exposed for 4 days to TCDD, was detected in CD4 + CD8 + cells compared with controls. We suggest that TCDD affects thymic selection and directs the lineage commitment of CD4 + CD8 + thymocytes towards CD4 – CD8 + cells, possibly via up-regulation of the Notch1 gene.