Generation of alpha beta 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
S. Kronenberg et al., Generation of alpha beta 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, IMMUNOLOGY, 100(2), 2000, pp. 185-193
Gene-targeted mice lacking the beta(2) microglobulin gene (beta(2)m(-/-) mi
ce), and hence functional major histocompatibility complex (MHC) class I mo
lecules, do not develop CD4(-) CD8(+) cells. We show here that both in vitr
o 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 beta(2)m(-/-) dams were given a single dose of 50 mu
g of TCDD, approximate to 13% of CD4(-) CD8(+) thymocytes could be detecte
d in their newborn pups. In TCDD-exposed fetal thymus organ cultures of bet
a(2)m(-/-) mice, approximate to 35% CD4(-) CD8(+) thymocytes were detectabl
e. About 16% of these CD4(-) CD8(+) cells bore the alpha beta T-cell recept
or (TCR) and approximate to 33% bore CD3. Only a minority of the CD8(+) cel
ls were heat-shock antigen positive. The cells possessed killing activity a
s shown using the Cr-51-release assay comprising gamma delta TCR- CD4(-) CD
8(+) thymocytes from 3 to 4-day-old beta(2)m(-/-) mice. Thus, TCDD leads to
a significant increase of mature CD4(-) CD8(+) thymocytes in relative and
absolute numbers. High numbers of CD4(-) CD8(+) thymocytes developed also i
n organ cultures from thymi, lacking both MHC class I and class II molecule
s, exposed to TCDD. A 10-fold transient increase of Notch1 mRNA in thymocyt
es from fetal thymus organ culture, exposed for 4 days to TCDD, was detecte
d in CD4(+) CD8(+) cells compared with controls. We suggest that TCDD affec
ts thymic selection and directs the lineage commitment of CD4(+) CD8(+) thy
mocytes towards CD4(-) CD8(+) cells, possibly via up-regulation of the Notc
h1 gene.