2,3,7,8-tetrachlorodibenzo-p-dioxin afters the differentiation of alloreactive CD8(+) T cells toward a regulatory T cell phenotype by a mechanism that is dependent on aryl hydrocarbon receptor in CD4(+) T cells

Activation of aryl hydrocarbon receptor (AhR) by 2,3,7,8-tetracholordibenzo-p-dioxin (TCDD) during an acute graft-versus-host response induces a population of alloreactive donor CD4(+)CD25(+) regulatory T (Treg)-like cells that have potent suppressive activity in vitro. In the present studies, we show that TCDD induced a similar population of donor CD8(+)CD25(+) T-cells with suppressive activity in vitro. Like the CD4(+) Treg cells, donor CD8(+)CD25(+) T-cells also expressed higher levels of CD28, glucocorticoid-induced TNFR (GITR) and CTLA-4 along with low levels of CD62L. These TCDD-induced phenotypic changes were not observed if donor T-cells were obtained from AhR-KO mice. When CD4(+) and CD8(+) donor T-cells from AhR-WT and AhR-KO mice were injected in various combinations into F1 mice, the enhanced expression of CD25 on CD8(+) T-cells required AhR in donor CD4+ T-cells, while down-regulation of CD62L required AhR in the donor CD8(+) T-cells themselves. Changes in GITR and CTLA-4 on donor CD8(+) T-cells were partially mediated by AhR in both T-cells subsets. In contrast, all phenotypic changes in donor CD4(+) T-cells were dependent on the presence of AhR in the CD4(+) T-cells themselves. These findings suggest that the direct effects of AhR-mediated signaling in CD8(+) T-cells are more limited than the direct effects in CD4(+) T-cells, and that AhR signaling in CD4(+) T-cells may be a unique pathway for the induction of both CD4(+) and CD8(+) adaptive Treg.