Short Communication: Resistance to Tumor Necrosis Factor-α-Induced Apoptosis in Human T-Lymphotropic Virus Type I-Infected T Cell Lines

Abstract

Induction of apoptosis of virus-infected cells is an important host cell defense mechanism. It is well documented that T cells may undergo apoptosis due to interactions between Fas and Fas ligand (FasL). In addition, signals that induce apoptosis in T cells can result from interaction of tumor necrosis factor (TNF)-alpha with TNF receptors (TNFRs). It has been shown that human T cell lines expressing HTLV-I have decreased sensitivity to Fas-mediated apoptosis. The susceptibility of HTLV-I-infected cells to TNF-alpha-induced apoptosis remains to be elucidated. In the present study, we examined the expression of TNFRs on HTLV-I-infected T cell lines that expressed T-cell activation markers and thus phenotypically resemble activated T cells. Different from primary activated T cells that expressed both TNFRs, none of the five HTLV-I-infected T cell lines studied had detectable TNFR1 and only three had TNFR2 on their cell surfaces, although, the RNA transcripts of both TNFR genes could be detected via reverse transcription-polymerase chain reaction in these cell lines. The T cell blasts, which we activated in vitro, were sensitive to apoptosis induced by TNF-alpha and by antibodies to TNFR1 and/or TNFR2. However, all of the HTLV-I-infected cell lines expressing TNFR2 were resistant to TNF-alpha-mediated apoptosis. These findings suggest that HTLV-I infection may interfere with the autonomous suicide programs of T cells, not only Fas/FasL but also TNFRs/TNF-alpha pathways, to prolong the life of the infected cells. This may contribute to viral persistence and favor survival and subsequent expansion of dysregulated infected T cells with the potential to produce HTLV-I-associated autoimmune-like diseases or malignancies.

Polymorphism and expression of the tumor necrosis factor receptor II gene in cows infected with the bovine leukemia virus

“…The first intron is known to regulate the expression of some genes, and mutations in this region can influence the level of their expression (Tsukada et al 2006, Yudin et alcould contribute to the pathogenesis of EBL (Konnai et al 2006). TNF-RII has also been suggested as a factor stimulating cell proliferation and inhibiting apoptosis (Yang et al 2002, Cui et al 2008. Nevertheless, reasons for changes in TNF-RII expression in peripheral blood mononuclear cells (PBMC) sampled from animals infected with BLV and during the progression of EBL have not been explained.…”

Short Communication Sequence analysis of the regulatory region of the TNF-RII gene in Polish Holstein-Friesian cows

“…A study of T lymphocytes in human subjects infected with HTLV-I revealed increased expression levels of TNF-RII but not TNF-RI. The study also demonstrated that cells sampled from patients infected with the above virus were less likely to undergo apoptosis induced by TNF-α (Yang et al, 2002). In cattle, the gene encoding TNF-RII has been localized on chromosome 16.…”

Modulation of apoptosis during HTLV‐1‐mediated immortalization process in vitro

“…Thus, apparently, modulation of apoptosis plays a crucial role in the balance between cell growth and cell death that leads to the process of immortalization of PBLs in vitro by HTLV-1. HTLV-1 transformed cells in the long-term were found to be resistant to TNFa-or Fas-induced apoptosis independently of TNF or Fas receptor expression [Kongphanich et al, 2002;Yang et al, 2002]. In particular, it was shown that resistance to Fas-mediated apoptosis in HTLV-1-infected cell lines might be dependent on the failure of Fas receptor clustering and caspase-8 activation, and that this could be overcome by treatment with cycloheximide [Kongphanich et al, 2002].…”

“…It has been hypothesized that induction of apoptosis might depend on nuclear expression of the CREB-binding protein (CBP)/p300-binding domain of the HTLV-1 transactivator Tax [Nicot and Harrod, 2000]. Conversely, it has been shown that HTLV-1-expressing human T-cell lines showed reduced susceptibility to anti-Fas [Copeland et al, 1994], and to TNFa stimulation [Yang et al, 2002]. This resistance to apoptosis might be due to the activation of NF-kB via Tax protein in HTLV-1 infected cells [Kawakami et al, 1999], to Tax-induced expression of anti-apoptotic genes [Brauweiler et al, 1997;Mori et al, 2001] and should involve p21 [Kawata et al, 2003].…”