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.
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.
Funatake
Castle J
CJ
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, USA. cfunatake@ucsd.edu
Marshall
Nikki B
NB
Kerkvliet
Nancy I
NI
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D006086:Graft vs Host Disease / Q000276:immunology; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000276:immunology* / Q000494:pharmacology; D007167:Immunotherapy; D053645:Interleukin-2 Receptor alpha Subunit; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000276:immunology* / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000276:immunology*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology
D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon