TNF-alpha mediated apoptosis of CD4 positive T-lymphocytes. A model of T-cell depletion in HIV infected individuals.
Apoptosis has been suggested to account for loss of CD4+ T-cells in HIV infected individuals. Aside from MHC II dependent superantigens no mediator for preferential apoptosis of CD4+ T-cell has been described. However, the expression of TNF-alpha is increased in HIV+ patients. Additionally, TNF-alpha is known as a potent inducer of apoptosis in a variety of cell types. We therefore investigated the capacity of TNF-alpha to mediate apoptosis in vitro preferentially in CD4+ T-cells from HIV+ individuals. In the presence of TNF-alpha, CD4+ T-cells from HIV+ individuals with more than 200 CD4+ T-cells/microl (classified CDC A1, A2, B1, B2) could be significantly depleted by apoptosis without a reduction of CD8+ T-cells. In cells from patients with less than 100 CD4+ T-cells/microl (classified CDC C3), TNF-alpha mediated apoptosis was not apparent due to an already immensely elevated rate of apoptosis observed in the absence of TNF-alpha. Here we demonstrate cord blood mononuclear cells as a model for apoptosis since these cells develop apoptosis at a similar rate as that of PBMC in HIV+ patients. More than 50% of TNF-alpha stimulated CD4+ cord blood T-cells were depleted within 3 days by apoptosis, whereas CD8+ T-cells, B-cells and NK-cells were not affected. In PBMC from healthy adults, a preferential loss of CD4+ T-cells mediated by TNF-alpha was not observed. A reduced production of IFN-gamma was observed in mononuclear cells from newborns and from HIV+ patients. Moreover, IFN-gamma and IL-2 could prevent TNF-alpha mediated apoptosis. Therefore, a reduced Th1-cell-function may contribute to TNF-alpha mediated apoptosis of CD4+ T-cells from these donor groups. Taken together, the data suggest that TNF-alpha probably is a mediator of the loss of CD4+ T-cells in HIV infected patients in vivo.
Klein
S A
SA
Universit-atsklinik Frankfurt, Medizinische Klinik III, Theodor-Stern-Kai 7, Frankfurt D-60590, Germany.
Dobmeyer
J M
JM
Dobmeyer
T S
TS
Falke
D
D
Kabelitz
D
D
Friese
K
K
Helm
E B
EB
Hoelzer
D
D
Rossol-Voth
R
R
D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000276:immunology; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002478:Cells, Cultured; D005312:Fetal Blood / Q000276:immunology; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D018023:HIV Seronegativity / Q000276:immunology*; D006679:HIV Seropositivity / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D018448:Models, Immunological; D012016:Reference Values; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology*
D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma