Cell Proliferation Arrest within Intrathymic Lymphocyte Progenitor Cells Causes Thymic Atrophy Mediated by the Aryl Hydrocarbon Receptor

Abstract

Activation of the aryl hydrocarbon receptor (AHR), a basic helix-loop-helix transcription factor, in lymphocytes by the immunosuppressive environmental contaminant 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to cause thymic atrophy in every species studied. We set out to identify the specific hemopoietic cellular populations in which the AHR was activated to lead to thymic atrophy and to determine the effect of AHR activation in those cellular populations. Initially, we examined whether AHR activation in intrathymic dendritic cells could mediate TCDD-induced thymic atrophy. It was found that thymic atrophy occurred only when the AHR could be activated in the thymocytes but not hemopoietic-derived dendritic cells or other APCs. We next analyzed the effect of TCDD on the proliferation of thymocytes in vivo. There was a significant increase in the percentage of thymocytes in the G1 phase of the cell cycle and a significant decrease in the percentage of S plus G2/M thymocytes, especially in the CD4−CD8−CD3− triple-negative intrathymic progenitor cell population 24 h after exposure to 30 μg/kg TCDD. Furthermore, by 12 h after exposure to TCDD, we observed ∼60% reduction of 5-bromo-2′-deoxyuridine incorporation in specific intrathymic progenitor cell populations. This reduction persisted for at least 6 days. These data indicate that intrathymic progenitor cells are direct targets of TCDD in the thymus and suggest that TCDD causes thymic atrophy by reducing entrance into cell cycle in these populations.

Possible involvement of arylhydrocarbon receptor variants in TCDD-induced thymic atrophy and XRE-dependent transcriptional activity in Wistar Hannover GALAS rats

“…In contrast to our expectation based on in vivo of Jurkat T cells to the AhR variants although the variants decreased the percentage of GFP-positive cells (Fig.6). Although TCDD induces thymic atrophy in chimeric mice having AhR +/+ hemopoietic and AhR -/-stroma components, but not in those having AhR -/-hemopoietic and AhR +/+ stroma components (Laiosa et al, 2003;Staples et al, 1998), it has been reported that TCDD causes several effects on stromal cells, such as aggregation and differentiation of epithelium (De Waal et al, 1992Greenlee et al, 1985;Kremer et al, 1994) Thus, taken together with the present and previous studies, it is thought that the difference in susceptibility to the thymic atrophy could be explained by the effects of TCDD on cells other than thymic T cells.…”

“…First, previous studies using knock-out, chimeric and transgenic mice showed that thymic T cells are the main target of TCDD to induce thymic atrophy (Laiosa et al, 2003;Nohara et al, 2005;Staples et al, 1998). Second, being consistent with the effects of TCDD on T cells in the etiology of thymic atrophy shown in previous in vivo studies (Kamath et al, 1997;Laiosa et al, 2003), Jurkat T cells having constitutively active AhR showed cell cycle arrest and apoptosis (Ito et al, 2004). Third, the suppression of the growth of Jurkat T cells having constitutively active AhR has been shown to be caused by both XRE-dependent and XRE-independent mechanisms (Ito et al, 2004).…”

“…It is thus conjectured that possible differences in the physical interaction between either of the AhR variants and functional proteins induce differences in the susceptibility of thymic atrophy among rat strains. Toxicity mechanisms of the TCDD-elicited thymic atrophy, the cell cycle arrest and apoptosis of thymic T cells have been proposed (Kamath et al, 1997;Laiosa et al, 2003). To this end, we hypothesized that AhR structural differences are associated with the difference in susceptibility to TCDD-induced thymic atrophy observed in vivo, and studied how AhR variants, i.e., AhRwt, AhRdv, AhRsiv and AhRliv, affect the growth of T cells, by transfecting these AhR variant genes into AhR-null Jurkat T cells.…”

“…11.3 ± 0. we used Jurkat T cells is that the exogenously introduced constitutively-active AhR suppresses the growth of the cells through apoptosis and cell cycle arrest (Ito et al, 2004), the observation of which is similar to the one in TCDD-exposed mice in vivo (Kamath et al, 1997;Laiosa et al, 2003).…”

Cancer immunoediting and dioxin-activating aryl hydrocarbon receptor: a missing link in the shift toward tumor immunoescape?

“…[57][58][59] Exposure to dioxin leads to profound suppression of both humoral and cellular immune responses. 60 Dioxin-activated AhR suppresses T-cells, which are its primary targets, and mediates B-cell antibody response inhibition [61][62][63] and thymic involution, with consequent thymocyte loss, premature migration of T-cell progenitors, [64][65][66] and overexpression of FAS-L in thymic stromal cells, resulting in Tcell apoptosis induction. 67,68 Alterations in thymocytes appear transient, as adult mice exposed developmentally to dioxin do not exhibit thymic atrophy or alterations in the proportion of thymocyte subpopulations, and skewing of T-cell subpopulations is not observed in secondary lymphoid organs.…”