Abstract
The correlates of protective immunity to disease-inducing viruses in man remain to be elucidated. We determined the kinetics and properties of cytomegalovirus (CMV)-specific CD4(+) T cells in healthy individuals and renal transplant recipients during different stages of CMV infection. Our data reveal that circulating CMV-specific CD4(+) T cells displayed an effector-memory phenotype, and produced the T helper 1 cytokines interferon-gamma and tumor necrosis factor-alpha. In addition, they lacked molecules for secondary lymphoid organ homing and expressed the cytotoxic molecule granzyme B, inferring a direct role of these cells at target sites of infection. In asymptomatic individuals the CMV-specific CD4(+) T-cell response preceded CMV-specific CD8(+) T-cell responses, whereas in symptomatic individuals the CMV-specific effector memory CD4(+) T-cell response was delayed and only detectable after antiviral therapy. The appearance of disease symptoms in these patients suggests that functional CD8(+) T cell and antibody responses are insufficient to control viral replication and that formation of effector memory CD4(+) T cells is necessary for recovery of infection.
MeSH terms
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ADP-ribosyl Cyclase / metabolism
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ADP-ribosyl Cyclase 1
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Antigens, CD / metabolism
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CD11a Antigen / metabolism
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CD4-Positive T-Lymphocytes / immunology*
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CD40 Ligand / metabolism
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CD8-Positive T-Lymphocytes / immunology
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Cross-Sectional Studies
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Cytomegalovirus Infections / etiology
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Cytomegalovirus Infections / immunology*
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DNA, Viral
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Flow Cytometry
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Granzymes
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Humans
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Immunoglobulin G / blood
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Immunoglobulin M / blood
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Immunosuppressive Agents / pharmacology
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Integrin alpha4 / metabolism
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Interferon-gamma / metabolism
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Interleukin-2 / metabolism
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Interleukin-4 / metabolism
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Ki-67 Antigen / metabolism
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Kidney Transplantation / adverse effects
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L-Selectin / metabolism
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Longitudinal Studies
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Membrane Glycoproteins
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Receptors, CCR7
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Receptors, Chemokine / metabolism
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Serine Endopeptidases / metabolism
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / metabolism
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Tumor Necrosis Factor-alpha / metabolism
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Viral Load
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Virus Latency / drug effects
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Virus Latency / immunology
Substances
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Antigens, CD
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CCR7 protein, human
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CD11a Antigen
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DNA, Viral
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Immunoglobulin G
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Immunoglobulin M
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Immunosuppressive Agents
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Interleukin-2
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Ki-67 Antigen
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Membrane Glycoproteins
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Receptors, CCR7
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Receptors, Chemokine
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Tumor Necrosis Factor Receptor Superfamily, Member 7
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Tumor Necrosis Factor-alpha
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L-Selectin
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Integrin alpha4
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CD40 Ligand
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Interleukin-4
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Interferon-gamma
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ADP-ribosyl Cyclase
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CD38 protein, human
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ADP-ribosyl Cyclase 1
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GZMB protein, human
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Granzymes
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Serine Endopeptidases