1. Increased sensitivity of T lymphocytes to tumor necrosis factor receptor 1 (TNFR1)- and TNFR2-mediated apoptosis in HIV infection: relation to expression of Bcl-2 and active caspase-8 and caspase-3.
- Author
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de Oliveira Pinto LM, Garcia S, Lecoeur H, Rapp C, and Gougeon ML
- Subjects
- Adult, Antibodies, Bispecific pharmacology, Antigens, CD immunology, Antigens, CD physiology, Apoptosis immunology, Case-Control Studies, Caspase 3, Caspase 8, Caspase 9, Caspases metabolism, Enzyme Activation, Female, HIV Infections pathology, Humans, Male, Middle Aged, Proto-Oncogene Proteins c-bcl-2 metabolism, Receptors, Tumor Necrosis Factor immunology, Receptors, Tumor Necrosis Factor physiology, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Signal Transduction drug effects, Signal Transduction immunology, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets enzymology, T-Lymphocyte Subsets virology, T-Lymphocytes cytology, T-Lymphocytes enzymology, Antigens, CD pharmacology, Apoptosis drug effects, HIV Infections immunology, T-Lymphocytes virology
- Abstract
The destruction of CD4 T cells in human immunodeficiency virus (HIV) infection is associated with activation of apoptotic programs, partly mediated by death receptors. The role of CD95L/CD95 in depletion of patients' CD4 T cells is well documented, but the possible contribution of the tumor necrosis factor/tumor necrosis factor receptor (TNF/TNFR) pathway has not been examined. In this study, we found that both TNFR1 and TNFR2 induced marked apoptosis in peripheral T cells from HIV-infected persons, involving both CD4 and CD8 T cells. Longitudinal follow-up of HIV(+) patients suggests an association between the in vivo evolution of CD4 T-cell numbers and variations in susceptibility to TNFR-induced apoptosis. Analysis of molecular mechanisms involved showed that it was not related to altered ex vivo expression of TNFR1-associated death domain, receptor interacting protein, or TNFR-associated factor 2. Susceptibility to TNFR-mediated apoptosis was rather related to Bcl-2 expression, because patients' T cells expressing high levels of Bcl-2 were completely protected from TNFR1- and TNFR2-induced cell death, whereas T cells expressing normal levels of Bcl-2 were not protected in patients in contrast to controls. Early recruitment of caspase-8 and caspase-3 is needed to transduce the apoptotic signals, and expression of both caspases in their active form was detected in blood T cells from HIV(+) patients, whereas it was hardly detected in controls. Moreover, ligation of TNFRs induced increased activation of both caspases in patients' T cells. Together these data demonstrate that exacerbated TNFR-mediated cell death of T cells from HIV-infected individuals is associated with both alteration of Bcl-2 expression and activation of caspase-8 and caspase-3 and may contribute to the pathogenesis of acquired immunodeficiency syndrome.
- Published
- 2002
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