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Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor.

Badley AD, Dockrell D, Simpson M, Schut R, Lynch DH, Leibson P, Paya CV - J. Exp. Med. (1997)

Bottom Line: This study addresses whether antigen-presenting cells such as human macrophages mediate apoptosis of CD4+ T cells from HIV-infected individuals.Uninfected human macrophages, and to a larger degree, HIV-infected macrophages mediate apoptosis of T cells from HIV-infected, but not from uninfected control individuals.These results support a role for macrophage-associated FasL and TNF in the selective depletion of CD4+ T cells in HIV-infected individuals.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota 55901, USA.

ABSTRACT
Apoptosis of bystander uninfected CD4+ T lymphocytes by neighboring HIV-infected cells is observed in cell culture and in lymphoid tissue of HIV-infected individuals. This study addresses whether antigen-presenting cells such as human macrophages mediate apoptosis of CD4+ T cells from HIV-infected individuals. Uninfected human macrophages, and to a larger degree, HIV-infected macrophages mediate apoptosis of T cells from HIV-infected, but not from uninfected control individuals. This macrophage-dependent killing targets CD4+, but not CD8+ T lymphocytes from HIV-infected individuals, and direct contact between macrophages and lymphocytes is required. Additional analyses indicated that the apoptosis-inducing ligands, FasL and tumor necrosis factor (TNF), mediate this macrophage-induced apoptosis of CD4+ T cells. These results support a role for macrophage-associated FasL and TNF in the selective depletion of CD4+ T cells in HIV-infected individuals.

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FasL and TNF participate in MDM-induced apoptosis of CD4+ T cells from HIV-infected individuals. 5 × 106 uninfected (NI) or HIV- infected (HIV) macrophages were incubated with 106 PBL from five different HIV-infected individuals in the presence or absence of 20 μg FasFc,  TNFRFc, or CD40Fc or 10 μg of each of TNFRFc and FasFc for 48 h. Analysis of CD4+ T cell apoptosis was done as described in Fig. 1 A. Observed  amounts of apoptosis for CD4 T cells are shown. Mean spontaneous apoptosis was 23.5 ± 9.8%.
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Figure 5: FasL and TNF participate in MDM-induced apoptosis of CD4+ T cells from HIV-infected individuals. 5 × 106 uninfected (NI) or HIV- infected (HIV) macrophages were incubated with 106 PBL from five different HIV-infected individuals in the presence or absence of 20 μg FasFc, TNFRFc, or CD40Fc or 10 μg of each of TNFRFc and FasFc for 48 h. Analysis of CD4+ T cell apoptosis was done as described in Fig. 1 A. Observed amounts of apoptosis for CD4 T cells are shown. Mean spontaneous apoptosis was 23.5 ± 9.8%.

Mentions: TNF is present as a soluble or cell membrane bound form (6), is produced by macrophages (42), and, as for FasL, can cause apoptosis of activated T cells (8, 9). To determine whether TNF participates in the apoptosis of CD4+ T lymphocytes mediated by MDM, PBLs from five HIV-infected individuals were coincubated with uninfected and HIV-infected MDM for 48 h in the presence or absence of the human TNFRFc fusion protein. This incubation period was selected to allow for possible differences in the timing of induction of T lymphocyte apoptosis by FasL and TNF (9). In parallel, we tested possible additive or synergistic effects between TNF and FasL using FasFc fusion proteins. As shown in Fig. 5, FasFc inhibited the HIV-MDM induced apoptosis of CD4+ T lymphocytes from the five HIV-infected individuals (compare lanes 2 and 3). However, TNFRFc also reduced CD4+ T cell apoptosis from the same individuals to a similar degree to that observed with FasFc (compare lanes 2–4). Interestingly, combining of TNFRFc and FasFc resulted in an additive inhibition of HIV-MDM mediated apoptosis of CD4+ T cells (lane 5). CD40Fc, included to control for the specificity of fusion protein dependent inhibition, reduced the MDM-mediated apoptosis of CD4+ T cells in three patients, albeit to a lower degree than FasFc or TNFRFc (lane 6). Altogether, these results indicate that FasL and TNF participate in the selective apoptosis of CD4+ T cells from HIV-infected individuals mediated by human macrophages.


Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor.

Badley AD, Dockrell D, Simpson M, Schut R, Lynch DH, Leibson P, Paya CV - J. Exp. Med. (1997)

FasL and TNF participate in MDM-induced apoptosis of CD4+ T cells from HIV-infected individuals. 5 × 106 uninfected (NI) or HIV- infected (HIV) macrophages were incubated with 106 PBL from five different HIV-infected individuals in the presence or absence of 20 μg FasFc,  TNFRFc, or CD40Fc or 10 μg of each of TNFRFc and FasFc for 48 h. Analysis of CD4+ T cell apoptosis was done as described in Fig. 1 A. Observed  amounts of apoptosis for CD4 T cells are shown. Mean spontaneous apoptosis was 23.5 ± 9.8%.
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Related In: Results  -  Collection

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Figure 5: FasL and TNF participate in MDM-induced apoptosis of CD4+ T cells from HIV-infected individuals. 5 × 106 uninfected (NI) or HIV- infected (HIV) macrophages were incubated with 106 PBL from five different HIV-infected individuals in the presence or absence of 20 μg FasFc, TNFRFc, or CD40Fc or 10 μg of each of TNFRFc and FasFc for 48 h. Analysis of CD4+ T cell apoptosis was done as described in Fig. 1 A. Observed amounts of apoptosis for CD4 T cells are shown. Mean spontaneous apoptosis was 23.5 ± 9.8%.
Mentions: TNF is present as a soluble or cell membrane bound form (6), is produced by macrophages (42), and, as for FasL, can cause apoptosis of activated T cells (8, 9). To determine whether TNF participates in the apoptosis of CD4+ T lymphocytes mediated by MDM, PBLs from five HIV-infected individuals were coincubated with uninfected and HIV-infected MDM for 48 h in the presence or absence of the human TNFRFc fusion protein. This incubation period was selected to allow for possible differences in the timing of induction of T lymphocyte apoptosis by FasL and TNF (9). In parallel, we tested possible additive or synergistic effects between TNF and FasL using FasFc fusion proteins. As shown in Fig. 5, FasFc inhibited the HIV-MDM induced apoptosis of CD4+ T lymphocytes from the five HIV-infected individuals (compare lanes 2 and 3). However, TNFRFc also reduced CD4+ T cell apoptosis from the same individuals to a similar degree to that observed with FasFc (compare lanes 2–4). Interestingly, combining of TNFRFc and FasFc resulted in an additive inhibition of HIV-MDM mediated apoptosis of CD4+ T cells (lane 5). CD40Fc, included to control for the specificity of fusion protein dependent inhibition, reduced the MDM-mediated apoptosis of CD4+ T cells in three patients, albeit to a lower degree than FasFc or TNFRFc (lane 6). Altogether, these results indicate that FasL and TNF participate in the selective apoptosis of CD4+ T cells from HIV-infected individuals mediated by human macrophages.

Bottom Line: This study addresses whether antigen-presenting cells such as human macrophages mediate apoptosis of CD4+ T cells from HIV-infected individuals.Uninfected human macrophages, and to a larger degree, HIV-infected macrophages mediate apoptosis of T cells from HIV-infected, but not from uninfected control individuals.These results support a role for macrophage-associated FasL and TNF in the selective depletion of CD4+ T cells in HIV-infected individuals.

View Article: PubMed Central - PubMed

Affiliation: Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota 55901, USA.

ABSTRACT
Apoptosis of bystander uninfected CD4+ T lymphocytes by neighboring HIV-infected cells is observed in cell culture and in lymphoid tissue of HIV-infected individuals. This study addresses whether antigen-presenting cells such as human macrophages mediate apoptosis of CD4+ T cells from HIV-infected individuals. Uninfected human macrophages, and to a larger degree, HIV-infected macrophages mediate apoptosis of T cells from HIV-infected, but not from uninfected control individuals. This macrophage-dependent killing targets CD4+, but not CD8+ T lymphocytes from HIV-infected individuals, and direct contact between macrophages and lymphocytes is required. Additional analyses indicated that the apoptosis-inducing ligands, FasL and tumor necrosis factor (TNF), mediate this macrophage-induced apoptosis of CD4+ T cells. These results support a role for macrophage-associated FasL and TNF in the selective depletion of CD4+ T cells in HIV-infected individuals.

Show MeSH
Related in: MedlinePlus