Abstract
The role of CD4+ T cells in the control of persistent viral infections beyond the provision of cognate help remains unclear. We used polychromatic flow cytometry to evaluate the production of the cytokines interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2, the chemokine macrophage inflammatory protein (MIP)-1beta, and surface mobilization of the degranulation marker CD107a by CD4+ T cells in response to stimulation with cytomegalovirus (CMV)-specific major histocompatibility complex class II peptide epitopes. Surface expression of CD45RO, CD27, and CD57 on responding cells was used to classify CD4+ T cell maturation. The functional profile of virus-specific CD4+ T cells in chronic CMV infection was unique compared with that observed in other viral infections. Salient features of this profile were: (a) the simultaneous production of MIP-1beta, TNF-alpha, and IFN-gamma in the absence of IL-2; and (b) direct cytolytic activity associated with surface mobilization of CD107a and intracellular expression of perforin and granzymes. This polyfunctional profile was associated with a terminally differentiated phenotype that was not characterized by a distinct clonotypic composition. Thus, mature CMV-specific CD4+ T cells exhibit distinct functional properties reminiscent of antiviral CD8+ T lymphocytes.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Adult
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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CD40 Ligand / metabolism
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CD57 Antigens / immunology
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Cell Differentiation / immunology*
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Chemokine CCL4
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Cytomegalovirus / immunology*
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Cytotoxicity, Immunologic / immunology*
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Epitopes, T-Lymphocyte / immunology
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Female
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Gene Products, gag / immunology
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Granzymes / metabolism
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Humans
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Interferon-gamma / metabolism
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / metabolism
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Lymphocyte Activation / immunology
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Lysosomal-Associated Membrane Protein 1 / metabolism
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Macrophage Inflammatory Proteins / metabolism
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Male
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Membrane Glycoproteins / metabolism
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Middle Aged
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Perforin
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Pore Forming Cytotoxic Proteins / metabolism
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T-Cell Antigen Receptor Specificity / immunology
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology
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Tumor Necrosis Factor-alpha / metabolism
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Vaccinia virus / immunology
Substances
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CD57 Antigens
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Chemokine CCL4
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Epitopes, T-Lymphocyte
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Gene Products, gag
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Lysosomal-Associated Membrane Protein 1
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Macrophage Inflammatory Proteins
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Membrane Glycoproteins
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Pore Forming Cytotoxic Proteins
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Tumor Necrosis Factor Receptor Superfamily, Member 7
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Tumor Necrosis Factor-alpha
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Perforin
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CD40 Ligand
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Interferon-gamma
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Granzymes