Expression of constitutively-active aryl hydrocarbon receptor in T-cells enhances the down-regulation of CD62L, but does not alter expression of CD25 or suppress the allogeneic CTL response

Abstract

Activation of aryl hydrocarbon receptor (AhR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in T-cells is required for TCDD-induced suppression of the allogeneic CTL response and for induction of CD25(hi)CD62L(low) adaptive regulatory T-cells. Here, the ability of a constitutively-active AhR (CA-AhR) expressed in T-cells alone to replicate the effects of TCDD was examined. The response of CA-AhR-expressing B6 donor T-cells in B6xD2F1 mice was compared to the response of wild-type B6 donor T-cells in B6xD2F1 mice given a single dose of TCDD. Expression of CA-AhR in donor T-cells enhanced the down-regulation of CD62L on Day 2 after injection, similar to a single oral dose of TCDD, but did not induce up-regulation of CD25 on Day 2 or affect CTL activity on Day 10. This suggests that activation of AhR in T-cells alone may not be sufficient to alter T-cell responses in this acute graft-versus-host (GvH) model. Since host APC are responsible for activating the donor T-cells, we examined the influence of the F1 host's AhR on donor T-cell responses by creating an AhR(-/-) B6xD2F1 host that had a greatly diminished AhR response to TCDD compared to wild-type F1 mice. As in AhR(+/+) B6xD2F1 mice, the CTL response in AhR(-/-) B6xD2F1 mice was completely suppressed by TCDD. This suggests that either CA-AhR dose not fully replicate the function of TCDD-activated AhR in suppression of the CTL response, or that minimal activation of AhR in host cells is required to combine with activation of AhR in T-cells to elicit the immunosuppressive effects of TCDD.

The aryl hydrocarbon receptor: fine-tuning the immune-response

“…AhR-dependent induction of iTreg is in contrast with studies using a T cell-specific constitutively active form of AhR, which does not result in increased Treg differentiation or development [34,35]. Importantly, increases in Treg in vivo have only been reported proportionally and not in absolute numbers, whilst other ligands such as FICZ reduce in vitro TGFb-dependent iTreg differentiation [31 ].…”

“…TCDD-mediated immune suppression is preceded by rapid proliferation followed by premature loss of CD4 + T cells [34], suggesting that strong activation of T cells does occur. However, the response may be actively terminated to prevent immune pathology and, possibly, morbidity.…”

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

“…Originally, the phenomena were explained by an induction of Tregs, but reports on direct FoxP3 induction by TCDD in vivo and in vitro are conflicting (Quintana et al, 2008;Duarte et al, 2013), and no enhancement of Tregs was evident in mice engineered to have a constitutively active AhR in T cells (Quintana et al, 2008;Funatake et al, 2009). DCs provide the milieu for T-cell differentiation in vivo, and AhR activation is involved in their tolerogenicity (Hauben et al, 2008;Nguyen et al, 2010).…”

Programmed Death-1 Shapes Memory Phenotype CD8 T Cell Subsets in a Cell-Intrinsic Manner

“…Differentially expressed transcription factors included Rel, STAT1, Irf4, Icrf8, and the less characterized Atf3, Ahr, and Bhlhe40 (Dec1). Ahr is able to modulate CD62L expression in primary responses (40) and under certain conditions it diminishes memory CD8 pool but not CD8 cell responses (41). Bhlhe40 transcription factor, which has recently been shown to be important in generation of regulatory T cells (42), is one of the most upregulated genes in PD-1 KO T CM CD8 cells (3.8-fold).…”