HTLV-I infection of WE17/10 CD4+ cell line leads to progressive alteration of Ca2+ influx that eventually results in loss of CD7 expression and activation of an antiapoptotic pathway involving AKT and BAD which paves the way for malignant transformation

Abstract

Adult T-cell leukemia/lymphoma (ATLL) is a malignancy slowly emerging from human T-cell leukemia virus type 1 (HTLV-I)-infected mature CD4 þ T-cells. To characterize the molecular modifications induced by HTLV-I infection, we compared HTLV-I-infected WE17/10 cells with control cells, using micro-arrays. Many calcium-related genes were progressively downmodulated over a period of 2 years. Infected cells acquired a profound decrease of intracellular calcium levels in response to ionomycin, timely correlated with decreased CD7 expression. Focusing on apoptosis-related genes and their relationship with CD7, we observed an underexpression of most antiapoptotic genes. Western blotting revealed increasing Akt and Bad phosphorylation, timely correlated with CD7 loss. This was shown to be phosphatidylinositol 3-kinase (PI3K)-dependent. Activation of PI3K/Akt induced resistance to the apoptotic effect of interleukin-2 deprivation. We thus propose the following model: HTLV-I infection induces a progressive decrease in CD3 genes expression, which eventually abrogates CD3 expression; loss of CD3 is known to perturb calcium transport. This perturbation correlates with loss of CD7 expression and induction of Akt and Bad phosphorylation via activation of PI3K. The activation of the Akt/Bad pathway generates a progressive resistance to apoptosis, at a time HTLV-I genes expression is silenced, thus avoiding immune surveillance. This could be a major event in the process of the malignant transformation into ATLL.

Single-Cell Mass Cytometry Analysis of Human Tonsil T Cell Remodeling by Varicella Zoster Virus

“…Reduced CD7 was consistent with decreased CD3ε expression on the V+ T cells compared to the UI/Bys T cells (Fig.2E); low CD3ε causes calcium perturbation that mediates CD7 loss (Akl et al, 2007b). In contrast, the CD3δ isoform was unaltered on V+ T cells (Fig.S2C).…”

Orexins/hypocretins and orexin receptors in apoptosis: a mini‐review

“…2006). Based on observations made on orexin receptor signalling or on apoptosis in immune cells expressing immunoreceptors equipped with tyrosine‐based motifs, other key enzymes and/or transcription factors may also be involved in OX1R‐mediated apoptosis such as, for example, signal transducer and activator of transcription 5 (STAT5), Akt kinase and/or ERK1/2 (Akl et al. 2007, Ramanjaneya et al.…”

“…The intracellular signalling pathways downstream of SHP-2 may include the p38 mitogen-/stressactivated protein kinase as the p38 inhibitor SB203580 inhibits orexin-mediated cell death in transfected CHO cells (Ammoun et al 2006). Based on observations made on orexin receptor signalling or on apoptosis in immune cells expressing immunoreceptors equipped with tyrosine-based motifs, other key enzymes and/or transcription factors may also be involved in OX1Rmediated apoptosis such as, for example, signal transducer and activator of transcription 5 (STAT5), Akt kinase and/or ERK1/2 (Akl et al 2007, Voisin et al 2008).…”

Human T-lymphotropic virus proteins and post-translational modification pathways

“…Active Akt promotes phosphorylation and inactivation of Bcl-2-associated death promoter protein (Bad), a pro-apoptotic protein [39] . Consistently, PI3K/Akt activation induces resistance to IL-2 deprivation in HTLV-1-infected cells, promoting a progressive resistance to apoptosis [121] .…”