Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin

Mario Clerici; Apurva Sarin; Jay A. Berzofsky; Alan L. Landay; Harold A. Kessler; Farah Hashemi; Craig W. Hendrix; Stephen P. Blatt; Janice Rusnak; Matthew J. Dolan; Robert L. Coffman; Pierre A. Henkart; Gene M. Shearer

doi:10.1097/00002030-199606000-00005

Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin

Mario Clerici, Apurva Sarin, Jay A. Berzofsky, Alan L. Landay, Harold A. Kessler, Farah Hashemi, Craig W. Hendrix, Stephen P. Blatt, Janice Rusnak, Matthew J. Dolan, Robert L. Coffman, Pierre A. Henkart, Gene M. Shearer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

66 Scopus citations

Abstract

Objective: To characterize the mechanism of in vitro antigen-induced apoptotic T-cell death in the peripheral blood mononuclear cells (PBMC) of HIV-1-infected individuals. Design and methods: PBMC from HIV-1-infected and uninfected individuals were unstimulated or stimulated with HIV-1 envelope synthetic peptides (Env) or influenza A virus to determine the extent of antigen-stimulated apoptotic T-cell death, whether this death was limited to the CD4+ subset, and the effects of cytokines on T-cell death. Death was assessed by apoptotic nuclear morphology after 7 days of culture by fluorescence microscopy using a DNA-specific dye. Transwell cultures and supernatant transfers were utilized to test whether a soluble factor produced by HIV-positive PBMC induced death of HIV-negative T cells. Exogenous cytokines [interleukin (IL)-12, interferon (IFN)-γ, IL-4 and IL-10], as well as antibodies against endogenously produced cytokines (IL-4, IL-10, IL-12, and lymphotoxin) were tested for their ability to modulate death. Results: Antigenic stimulation induced death in PBMC from HIV-positive donors, but not in PBMC from HIV-negative donors. Antigen-stimulated death was seen in CD4+ but not CD8+ T-cell subset from the HIV-positive patients. Apoptotic death was blocked by IL-12, IFN-γ, anti-IL-4, anti-IL-10, and anti-lymphotoxin, but not by anti-IL-12. Transwell and supernatant transfer experiments indicated that antigen stimulated HIV-positive PBMC produced a factor that killed T-cell blasts. The factor was inhibited by anti-lymphotoxin, but not by anti-IL-10. Conclusions: Stimulation of HIV-positive PBMC with CD4-dependent antigens results in selective death of CD4+ T cells that is modulated by cytokines. Our results suggest that apoptotic death is not limited to HIV-infected or HIV-specific T cells, but occurs in bystander cells. Lymphotoxin is a mediator of antigen-stimulated T-cell death in this in vitro model.

Original language	English
Pages (from-to)	603-611
Number of pages	9
Journal	AIDS
Volume	10
Issue number	6
DOIs	https://doi.org/10.1097/00002030-199606000-00005
State	Published - 1996
Externally published	Yes

Keywords

Apoptosis
CD4+ T cells
Cytokines
HIV infection

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10.1097/00002030-199606000-00005

Cite this

Clerici, M., Sarin, A., Berzofsky, J. A., Landay, A. L., Kessler, H. A., Hashemi, F., Hendrix, C. W., Blatt, S. P., Rusnak, J., Dolan, M. J., Coffman, R. L., Henkart, P. A., & Shearer, G. M. (1996). Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin. AIDS, 10(6), 603-611. https://doi.org/10.1097/00002030-199606000-00005

@article{c97e986da300482e80ecd2292e52b44e,

title = "Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin",

abstract = "Objective: To characterize the mechanism of in vitro antigen-induced apoptotic T-cell death in the peripheral blood mononuclear cells (PBMC) of HIV-1-infected individuals. Design and methods: PBMC from HIV-1-infected and uninfected individuals were unstimulated or stimulated with HIV-1 envelope synthetic peptides (Env) or influenza A virus to determine the extent of antigen-stimulated apoptotic T-cell death, whether this death was limited to the CD4+ subset, and the effects of cytokines on T-cell death. Death was assessed by apoptotic nuclear morphology after 7 days of culture by fluorescence microscopy using a DNA-specific dye. Transwell cultures and supernatant transfers were utilized to test whether a soluble factor produced by HIV-positive PBMC induced death of HIV-negative T cells. Exogenous cytokines [interleukin (IL)-12, interferon (IFN)-γ, IL-4 and IL-10], as well as antibodies against endogenously produced cytokines (IL-4, IL-10, IL-12, and lymphotoxin) were tested for their ability to modulate death. Results: Antigenic stimulation induced death in PBMC from HIV-positive donors, but not in PBMC from HIV-negative donors. Antigen-stimulated death was seen in CD4+ but not CD8+ T-cell subset from the HIV-positive patients. Apoptotic death was blocked by IL-12, IFN-γ, anti-IL-4, anti-IL-10, and anti-lymphotoxin, but not by anti-IL-12. Transwell and supernatant transfer experiments indicated that antigen stimulated HIV-positive PBMC produced a factor that killed T-cell blasts. The factor was inhibited by anti-lymphotoxin, but not by anti-IL-10. Conclusions: Stimulation of HIV-positive PBMC with CD4-dependent antigens results in selective death of CD4+ T cells that is modulated by cytokines. Our results suggest that apoptotic death is not limited to HIV-infected or HIV-specific T cells, but occurs in bystander cells. Lymphotoxin is a mediator of antigen-stimulated T-cell death in this in vitro model.",

keywords = "Apoptosis, CD4+ T cells, Cytokines, HIV infection",

author = "Mario Clerici and Apurva Sarin and Berzofsky, {Jay A.} and Landay, {Alan L.} and Kessler, {Harold A.} and Farah Hashemi and Hendrix, {Craig W.} and Blatt, {Stephen P.} and Janice Rusnak and Dolan, {Matthew J.} and Coffman, {Robert L.} and Henkart, {Pierre A.} and Shearer, {Gene M.}",

year = "1996",

doi = "10.1097/00002030-199606000-00005",

language = "English",

volume = "10",

pages = "603--611",

journal = "AIDS",

issn = "0269-9370",

number = "6",

}

Clerici, M, Sarin, A, Berzofsky, JA, Landay, AL, Kessler, HA, Hashemi, F, Hendrix, CW, Blatt, SP, Rusnak, J, Dolan, MJ, Coffman, RL, Henkart, PA & Shearer, GM 1996, 'Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin', AIDS, vol. 10, no. 6, pp. 603-611. https://doi.org/10.1097/00002030-199606000-00005

TY - JOUR

T1 - Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin

AU - Clerici, Mario

AU - Sarin, Apurva

AU - Berzofsky, Jay A.

AU - Landay, Alan L.

AU - Kessler, Harold A.

AU - Hashemi, Farah

AU - Hendrix, Craig W.

AU - Blatt, Stephen P.

AU - Rusnak, Janice

AU - Dolan, Matthew J.

AU - Coffman, Robert L.

AU - Henkart, Pierre A.

AU - Shearer, Gene M.

PY - 1996

Y1 - 1996

N2 - Objective: To characterize the mechanism of in vitro antigen-induced apoptotic T-cell death in the peripheral blood mononuclear cells (PBMC) of HIV-1-infected individuals. Design and methods: PBMC from HIV-1-infected and uninfected individuals were unstimulated or stimulated with HIV-1 envelope synthetic peptides (Env) or influenza A virus to determine the extent of antigen-stimulated apoptotic T-cell death, whether this death was limited to the CD4+ subset, and the effects of cytokines on T-cell death. Death was assessed by apoptotic nuclear morphology after 7 days of culture by fluorescence microscopy using a DNA-specific dye. Transwell cultures and supernatant transfers were utilized to test whether a soluble factor produced by HIV-positive PBMC induced death of HIV-negative T cells. Exogenous cytokines [interleukin (IL)-12, interferon (IFN)-γ, IL-4 and IL-10], as well as antibodies against endogenously produced cytokines (IL-4, IL-10, IL-12, and lymphotoxin) were tested for their ability to modulate death. Results: Antigenic stimulation induced death in PBMC from HIV-positive donors, but not in PBMC from HIV-negative donors. Antigen-stimulated death was seen in CD4+ but not CD8+ T-cell subset from the HIV-positive patients. Apoptotic death was blocked by IL-12, IFN-γ, anti-IL-4, anti-IL-10, and anti-lymphotoxin, but not by anti-IL-12. Transwell and supernatant transfer experiments indicated that antigen stimulated HIV-positive PBMC produced a factor that killed T-cell blasts. The factor was inhibited by anti-lymphotoxin, but not by anti-IL-10. Conclusions: Stimulation of HIV-positive PBMC with CD4-dependent antigens results in selective death of CD4+ T cells that is modulated by cytokines. Our results suggest that apoptotic death is not limited to HIV-infected or HIV-specific T cells, but occurs in bystander cells. Lymphotoxin is a mediator of antigen-stimulated T-cell death in this in vitro model.

AB - Objective: To characterize the mechanism of in vitro antigen-induced apoptotic T-cell death in the peripheral blood mononuclear cells (PBMC) of HIV-1-infected individuals. Design and methods: PBMC from HIV-1-infected and uninfected individuals were unstimulated or stimulated with HIV-1 envelope synthetic peptides (Env) or influenza A virus to determine the extent of antigen-stimulated apoptotic T-cell death, whether this death was limited to the CD4+ subset, and the effects of cytokines on T-cell death. Death was assessed by apoptotic nuclear morphology after 7 days of culture by fluorescence microscopy using a DNA-specific dye. Transwell cultures and supernatant transfers were utilized to test whether a soluble factor produced by HIV-positive PBMC induced death of HIV-negative T cells. Exogenous cytokines [interleukin (IL)-12, interferon (IFN)-γ, IL-4 and IL-10], as well as antibodies against endogenously produced cytokines (IL-4, IL-10, IL-12, and lymphotoxin) were tested for their ability to modulate death. Results: Antigenic stimulation induced death in PBMC from HIV-positive donors, but not in PBMC from HIV-negative donors. Antigen-stimulated death was seen in CD4+ but not CD8+ T-cell subset from the HIV-positive patients. Apoptotic death was blocked by IL-12, IFN-γ, anti-IL-4, anti-IL-10, and anti-lymphotoxin, but not by anti-IL-12. Transwell and supernatant transfer experiments indicated that antigen stimulated HIV-positive PBMC produced a factor that killed T-cell blasts. The factor was inhibited by anti-lymphotoxin, but not by anti-IL-10. Conclusions: Stimulation of HIV-positive PBMC with CD4-dependent antigens results in selective death of CD4+ T cells that is modulated by cytokines. Our results suggest that apoptotic death is not limited to HIV-infected or HIV-specific T cells, but occurs in bystander cells. Lymphotoxin is a mediator of antigen-stimulated T-cell death in this in vitro model.

KW - Apoptosis

KW - CD4+ T cells

KW - Cytokines

KW - HIV infection

UR - http://www.scopus.com/inward/record.url?scp=9344261434&partnerID=8YFLogxK

U2 - 10.1097/00002030-199606000-00005

DO - 10.1097/00002030-199606000-00005

M3 - Article

C2 - 8780814

AN - SCOPUS:9344261434

SN - 0269-9370

VL - 10

SP - 603

EP - 611

JO - AIDS

JF - AIDS

IS - 6

ER -

Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin

Abstract

Keywords

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