Human immunodeficiency virus-specific circulating CD8 T lymphocytes have down-modulated CD3ζ and CD28, key signaling molecules for T-cell activation

L. A. Trimble, P. Shankar, M. Patterson, Johanna P. Daily, J. Lieberman

Research output: Contribution to journalArticle

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Abstract

Although human immunodeficiency virus (HIV)-infected subjects without AIDS have a high frequency of HIV-specific CD8 T lymphocytes, cellular immunity is unable to control infection. Freshly isolated lymphocytes often do not lyse HIV-infected targets in 4-h cytotoxicity assays. A large fraction of circulating CD8 T cells from HIV. infected donors down-modulate CD3ζ, the signaling component of the T-cell receptor complex, which is reexpressed in vitro coincident with the return of cytotoxic function. To investigate further the link between CD3ζ down-modulation and possible CD8 T-cell functional defects, we used flow cytometry to characterize further the properties of the CD3ζ-down-modulated subset. HIV. specific CD8 T cells, identified by tetramer staining, are CD3ζ-. CD8 T cells with down-modulated CD3ζ also do not express the key costimulatory receptor CD28 and have the cell surface phenotype of activated or memory T cells (HLA-DR+ CD62L-). After T-cell activation, CD3ζ-down-modulated cells express the activation marker CD69 but not the high-affinity interleukin 2 (IL-2) receptor α-chain CD25 and produce gamma interferon but not IL-2. Therefore HIV. specific CD8 T cells have down-modulated key signaling molecules for T-cell activation and costimulation and require exogenous cytokine stimulation. The typical impairment of HIV-specific CD4 T helper cells, which would normally provide specific CD8 T-cell stimulation, means that in vivo CTL function in vivo is compromised in most HIV-infected individuals. In AIDS patients, the functional defect is more severe, since CD3ζ is not reexpressed even after IL-2 exposure.

Original languageEnglish (US)
Pages (from-to)7320-7330
Number of pages11
JournalJournal of Virology
Volume74
Issue number16
DOIs
StatePublished - 2000
Externally publishedYes

Fingerprint

Human immunodeficiency virus
T-lymphocytes
HIV
T-Lymphocytes
interleukin-2
Interleukin-2
Acquired Immunodeficiency Syndrome
receptors
Interleukin-2 Receptors
HLA-DR Antigens
Infection Control
Helper-Inducer T-Lymphocytes
T-Cell Antigen Receptor
Cellular Immunity
Interferon-gamma
interferon-gamma
Flow Cytometry
cell-mediated immunity
flow cytometry
cytotoxicity

ASJC Scopus subject areas

  • Immunology

Cite this

Human immunodeficiency virus-specific circulating CD8 T lymphocytes have down-modulated CD3ζ and CD28, key signaling molecules for T-cell activation. / Trimble, L. A.; Shankar, P.; Patterson, M.; Daily, Johanna P.; Lieberman, J.

In: Journal of Virology, Vol. 74, No. 16, 2000, p. 7320-7330.

Research output: Contribution to journalArticle

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abstract = "Although human immunodeficiency virus (HIV)-infected subjects without AIDS have a high frequency of HIV-specific CD8 T lymphocytes, cellular immunity is unable to control infection. Freshly isolated lymphocytes often do not lyse HIV-infected targets in 4-h cytotoxicity assays. A large fraction of circulating CD8 T cells from HIV. infected donors down-modulate CD3ζ, the signaling component of the T-cell receptor complex, which is reexpressed in vitro coincident with the return of cytotoxic function. To investigate further the link between CD3ζ down-modulation and possible CD8 T-cell functional defects, we used flow cytometry to characterize further the properties of the CD3ζ-down-modulated subset. HIV. specific CD8 T cells, identified by tetramer staining, are CD3ζ-. CD8 T cells with down-modulated CD3ζ also do not express the key costimulatory receptor CD28 and have the cell surface phenotype of activated or memory T cells (HLA-DR+ CD62L-). After T-cell activation, CD3ζ-down-modulated cells express the activation marker CD69 but not the high-affinity interleukin 2 (IL-2) receptor α-chain CD25 and produce gamma interferon but not IL-2. Therefore HIV. specific CD8 T cells have down-modulated key signaling molecules for T-cell activation and costimulation and require exogenous cytokine stimulation. The typical impairment of HIV-specific CD4 T helper cells, which would normally provide specific CD8 T-cell stimulation, means that in vivo CTL function in vivo is compromised in most HIV-infected individuals. In AIDS patients, the functional defect is more severe, since CD3ζ is not reexpressed even after IL-2 exposure.",
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