2,3,7,8-Tetrachlorodibenzo-p-dioxin Alters 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

Abstract

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.

Keywords :

• aryl hydrocarbon receptor
• CD8⁺ T-cells
• regulatory T-cells
• TCDD