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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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Apoptosis of CD4+ T cells  from HIV seropositive individuals by uninfected and HIV-infected macrophages. (A)  Analysis of apoptosis can be performed separately on CD4+ T lymphocytes (CD3 FITC  positive, CD4+ PE positive cells) and on  CD8+ lymphocytes (CD3 FITC positive,  CD4+ PE negative cells). In the plot depicted, 36.9% of cells have decreased forward angle light scatter and increased Hoechst  specific fluorescence, indicating that these  cells are apoptotic within the CD4 population (right). (B and C) Uninfected macrophages (UNINFECTED MDM) were used  as effector cells at 5:1 effector/target ratio  against PBL from either HIV seronegative  (B) or infected individuals (C). Mean spontaneous apoptosis was 7.8 ± 4.9% (B), and  23.1 ± 15.1% (C). (D and E) The same experiments repeated with HIV-infected  MDM (HIV-MDM) against HIV seronegative (D) or seropositive (E) individuals. Median spontaneous apoptosis was 8.1 ± 4.8%  (D), and 23.0 ± 14.8 (E). In B–E, percent  specific apoptosis was calculated by subtracting the amount of apoptosis from PBLs cultured in medium alone from the amount of  apoptosis when the same PBLs were coincubated with macrophages as indicated.
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Figure 1: Apoptosis of CD4+ T cells from HIV seropositive individuals by uninfected and HIV-infected macrophages. (A) Analysis of apoptosis can be performed separately on CD4+ T lymphocytes (CD3 FITC positive, CD4+ PE positive cells) and on CD8+ lymphocytes (CD3 FITC positive, CD4+ PE negative cells). In the plot depicted, 36.9% of cells have decreased forward angle light scatter and increased Hoechst specific fluorescence, indicating that these cells are apoptotic within the CD4 population (right). (B and C) Uninfected macrophages (UNINFECTED MDM) were used as effector cells at 5:1 effector/target ratio against PBL from either HIV seronegative (B) or infected individuals (C). Mean spontaneous apoptosis was 7.8 ± 4.9% (B), and 23.1 ± 15.1% (C). (D and E) The same experiments repeated with HIV-infected MDM (HIV-MDM) against HIV seronegative (D) or seropositive (E) individuals. Median spontaneous apoptosis was 8.1 ± 4.8% (D), and 23.0 ± 14.8 (E). In B–E, percent specific apoptosis was calculated by subtracting the amount of apoptosis from PBLs cultured in medium alone from the amount of apoptosis when the same PBLs were coincubated with macrophages as indicated.

Mentions: To determine whether MDM trigger apoptosis of CD4+ T cells, 14-d-old MDM from HIV seronegative healthy donors were incubated for 36 h with freshly isolated PBL from HIV-infected individuals or HIV seronegative healthy donors. Thereafter, nonadherent cells were harvested and analyzed using flow cytometry to detect apoptosis within CD4+ or CD8+ T lymphocytes. A representative example of this analysis is depicted in Fig. 1 A. A minimal degree of CD4+ T cell apoptosis (median of 1.25%) is observed in PBL from HIV seronegative healthy control donors (Fig. 1 B). However, when MDM are incubated with PBL from HIV-infected individuals, a larger degree of CD4+ T lymphocyte apoptosis is observed (median of 8.7%, P = 0.039) (Fig. 1 C), suggesting enhanced susceptibility of CD4+ T cells from HIV-infected individuals to MDM-mediated apoptosis.


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)

Apoptosis of CD4+ T cells  from HIV seropositive individuals by uninfected and HIV-infected macrophages. (A)  Analysis of apoptosis can be performed separately on CD4+ T lymphocytes (CD3 FITC  positive, CD4+ PE positive cells) and on  CD8+ lymphocytes (CD3 FITC positive,  CD4+ PE negative cells). In the plot depicted, 36.9% of cells have decreased forward angle light scatter and increased Hoechst  specific fluorescence, indicating that these  cells are apoptotic within the CD4 population (right). (B and C) Uninfected macrophages (UNINFECTED MDM) were used  as effector cells at 5:1 effector/target ratio  against PBL from either HIV seronegative  (B) or infected individuals (C). Mean spontaneous apoptosis was 7.8 ± 4.9% (B), and  23.1 ± 15.1% (C). (D and E) The same experiments repeated with HIV-infected  MDM (HIV-MDM) against HIV seronegative (D) or seropositive (E) individuals. Median spontaneous apoptosis was 8.1 ± 4.8%  (D), and 23.0 ± 14.8 (E). In B–E, percent  specific apoptosis was calculated by subtracting the amount of apoptosis from PBLs cultured in medium alone from the amount of  apoptosis when the same PBLs were coincubated with macrophages as indicated.
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Related In: Results  -  Collection

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Figure 1: Apoptosis of CD4+ T cells from HIV seropositive individuals by uninfected and HIV-infected macrophages. (A) Analysis of apoptosis can be performed separately on CD4+ T lymphocytes (CD3 FITC positive, CD4+ PE positive cells) and on CD8+ lymphocytes (CD3 FITC positive, CD4+ PE negative cells). In the plot depicted, 36.9% of cells have decreased forward angle light scatter and increased Hoechst specific fluorescence, indicating that these cells are apoptotic within the CD4 population (right). (B and C) Uninfected macrophages (UNINFECTED MDM) were used as effector cells at 5:1 effector/target ratio against PBL from either HIV seronegative (B) or infected individuals (C). Mean spontaneous apoptosis was 7.8 ± 4.9% (B), and 23.1 ± 15.1% (C). (D and E) The same experiments repeated with HIV-infected MDM (HIV-MDM) against HIV seronegative (D) or seropositive (E) individuals. Median spontaneous apoptosis was 8.1 ± 4.8% (D), and 23.0 ± 14.8 (E). In B–E, percent specific apoptosis was calculated by subtracting the amount of apoptosis from PBLs cultured in medium alone from the amount of apoptosis when the same PBLs were coincubated with macrophages as indicated.
Mentions: To determine whether MDM trigger apoptosis of CD4+ T cells, 14-d-old MDM from HIV seronegative healthy donors were incubated for 36 h with freshly isolated PBL from HIV-infected individuals or HIV seronegative healthy donors. Thereafter, nonadherent cells were harvested and analyzed using flow cytometry to detect apoptosis within CD4+ or CD8+ T lymphocytes. A representative example of this analysis is depicted in Fig. 1 A. A minimal degree of CD4+ T cell apoptosis (median of 1.25%) is observed in PBL from HIV seronegative healthy control donors (Fig. 1 B). However, when MDM are incubated with PBL from HIV-infected individuals, a larger degree of CD4+ T lymphocyte apoptosis is observed (median of 8.7%, P = 0.039) (Fig. 1 C), suggesting enhanced susceptibility of CD4+ T cells from HIV-infected individuals to MDM-mediated apoptosis.

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