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

J Immunotoxicol. 2008 Jan;5(1):81-91. doi: 10.1080/15476910802019037.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / immunology
  • Cell Proliferation / drug effects
  • Graft vs Host Disease / immunology
  • Immunophenotyping
  • Immunosuppressive Agents / immunology*
  • Immunosuppressive Agents / pharmacology
  • Immunotherapy
  • Interleukin-2 Receptor alpha Subunit
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Polychlorinated Dibenzodioxins / immunology*
  • Polychlorinated Dibenzodioxins / pharmacology
  • Receptors, Aryl Hydrocarbon / agonists
  • Receptors, Aryl Hydrocarbon / immunology*
  • Signal Transduction
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / immunology


  • Immunosuppressive Agents
  • Interleukin-2 Receptor alpha Subunit
  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon