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The integrin-triggered rescue of T lymphocyte apoptosis is blocked in HIV-1-infected individuals

Ng, TTC; Kanner, SB; Humphries, MJ; Wickremasinghe, RG; Nye, KE; Anderson, J; Khoo, SH; (1997) The integrin-triggered rescue of T lymphocyte apoptosis is blocked in HIV-1-infected individuals. J IMMUNOL , 158 (6) 2984 - 2999.

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Abstract

HIV infection is associated with a disease status-dependent impairment of Ag-specific T cell responses, resulting in anergy or unchecked apoptotic cell death, beta(1) integrins play an important role in the induction of T lymphocyte responses to antigenic challenge by providing a T cell costimulatory signal, and have been shown to rescue various cell types from undergoing apoptosis. We examined the integrin-triggered cell survival signal and associated pathways in CD3(+) T cells derived from 69 HIV-1-infected individuals in comparison with healthy controls. We found beta(1) integrin-mediated costimulation of TCR-induced T cell proliferation and protection from aberrant cell death to be absent in the majority of patients with AIDS, but intact in asymptomatic, infected individuals. The lack of integrin-mediated rescue may be partly due to an early impairment of TCR/integrin-costimulated secretion of IFN-gamma, a type 1 lymphokine that protects against TCR-induced apoptosis of T cells from HIV-seropositive donors, but not loss of integrin expression. The mechanism of integrin hyporesponsiveness appeared to correlate with a failure of the integrin-generated signal to induce pp125(FAK) mRNA and protein expression. Protein kinase C activation in CD3(+) T cells following integrin stimulation was also impaired in HIV-infected individuals, mostly among the symptomatic/AIDS patients. Protein kinase C inactivation in T cells was shown to have a destabilizing effect in vitro on pp125(FAK) mRNA that contains an AUUUA motif in the 3'-untranslated region, a consensus sequence for the AU-rich elements responsible for mRNA destabilization. These aberrant changes in pp125(FAK) expression may have direct significance to the overall immunopathogenesis during infection with HIV-1.

Type: Article
Title: The integrin-triggered rescue of T lymphocyte apoptosis is blocked in HIV-1-infected individuals
Keywords: PROTEIN-KINASE-C, FOCAL ADHESION KINASE, MESSENGER-RNA DEGRADATION, TYROSINE PHOSPHORYLATION, PERMISSIVE ACTIVATION, EXTRACELLULAR-MATRIX, MONOCLONAL-ANTIBODY, LYMPHOBLASTIC CELLS, SYNTHETIC PEPTIDE, SEQUENCE IDENTITY
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/121914
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