The integrin-triggered rescue of T lymphocyte apoptosis is blocked in HIV-1-infected individuals.
HIV infection is associated with a disease status-dependent impairment of Ag-specific T cell responses, resulting in anergy or unchecked apoptotic cell death. beta1 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 beta1 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 pp125FAK 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 pp125FAK 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 pp125FAK expression may have direct significance to the overall immunopathogenesis during infection with HIV-1.
Ng
T T
TT
Department of Immunology, St. Bartholomew's and Royal London School of Medicine and Dentistry, United Kingdom.
Kanner
S B
SB
Humphries
M J
MJ
Wickremasinghe
R G
RG
Nye
K E
KE
Anderson
J
J
Khoo
S H
SH
Morrow
W J
WJ
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology; D019380:Anti-HIV Agents / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D000939:Epitopes / Q000502:physiology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D019012:Integrin beta1 / Q000096:biosynthesis; D016023:Integrins / Q000378:metabolism / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism; D007399:Interphase; D007945:Leukemia, Lymphoid; D008213:Lymphocyte Activation / Q000187:drug effects; D011493:Protein Kinase C / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D000939:Epitopes; D019012:Integrin beta1; D016023:Integrins; D012333:RNA, Messenger; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D011493:Protein Kinase C