Toxin Targets T Cells

Abstract

The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, also referred to as dioxin) is a highly toxic environmental pollutant that acts by regulating a ligand-activated transcription factor known as the aryl hydrocarbon receptor (AHR), for which the endogenous regulatory ligand or ligands remain uncertain. Two papers report that the AHR has an important role in controlling T cell differentiation that could help explain increased prevalence of autoimmune diseases in industrialized countries in which exposure to environmental toxins may be a factor. T cells can differentiate into T reg cells, which help keep inflammation in check by inhibiting proliferation of effector cells and secretion of inflammatory cytokines, or T H 17 cells, which generally promote inflammation. Dioxin exposure suppresses immune responses, but the mechanism has been unclear. Quintana et al . made the connection of the AHR to T cell differentiation because the regulatory region near a gene that is highly expressed in T reg cells (Foxp3) contained an evolutionarily conserved binding site for the AHR. Veldhoen et al . noted that T H 17 cells specifically expressed AHRs. The latter group showed that activation of AHR increased expression of cytokines by T H 17 cells in vitro and that, in AHR-deficient mice, production of T H 17 cells was diminished when they induced experimental autoimmune encephalitis in the animals. Quintana et al . went on to show that AHR indeed directly regulated expression of Foxp3. Furthermore, in mice, their experiments showed that the AHR could promote either differentiation of T reg or T H 17 cells, depending on the ligand that was used to activate it. The authors note that this ligand-specific modulation of inflammatory responses could make AHR a particularly valuable therapeutic target for modulation of immune function. Stevens and Bradfield provide commentary. F. J. Quintana, A. S. Basso, A. H. Iglesias, T. Korn, M. F. Farez, E. Bettelli, M. Caccamo, M. Oukka, H. L. Weiner, Control of T reg and T H 17 cell differentiation by the aryl hydrocarbon receptor. Nature 453 , 65-71 (2008). [PubMed] M. Veldhoen, K. Hirota, A. M. Westendorf, J. Buer, L. Dumoutier, J.-C. Renauld, B. Stockinger, The aryl hydrocarbon receptor links T H 17-cell-mediated autoimmunity to environmental toxins. Nature 453 , 106-109 (2008). [PubMed] E. A. Stevens, C. A. Bradfield, T cells hang in the balance. Nature 453 , 46-47 (2008). [PubMed]