Journal
TOXICOLOGICAL SCIENCES
Volume 135, Issue 1, Pages 81-90Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kft140
Keywords
TCDD; IDO; CTLA-4; GVHD; T-regulatory cell
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Funding
- National Institutes of Health [5RO1ES016651]
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Activation of the aryl hydrocarbon receptor (AhR) by its prototypic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces potent suppression of an acute graft-versus-host (GVH) response and prevents GVH disease (GVHD). Suppression is associated with development of a regulatory population of donor CD4 CD25T-cells that express high levels of cytotoxic T-lymphocyte antigen 4 (CTLA-4). However, a direct link between these AhR-induced Tregs (AhR-Tregs) and suppression of GVHD remains to be shown. CTLA-4 is a negative regulator of T-cell responses and is associated with the induction of tolerogenic dendritic cells (DCs) that produce indoleamine 2,3-dioxygenase (IDO). We hypothesized that AhR-Tregs mediate suppression via their enhanced expression of CTLA-4, which, in turn, induces IFN- and IDO in host DCs. Subsequent depletion of tryptophan by IDO leads to termination of the donor T-cell response prior to development of effector CTL. Here, we show that despite increased expression of Ifng, Irf3, Irf7, Ido1, and Ido2 in the lymph nodes of TCDD-treated host mice, inhibition of IDO enzyme activity by 1-methyl-tryptophan was unable to relieve TCDD-mediated suppression of the GVH response. Furthermore, treatment with an anti-CTLA-4 antibody that blocks CTLA-4 signaling was also unable to alleviate TCDD-mediated suppression. Alternatively, we investigated the possibility that donor-derived AhR-Tregs produce IFN- to suppress effector CTL development. However, suppression of GVHD by TCDD was not affected by the use of Ifng-deficient donor cells. Together, these results indicate that neither overexpression of CTLA-4 nor production of IFN- by AhR-Tregs plays a major role in the manifestation of their immunosuppressive function in vivo.
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