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1.
J Leukoc Biol ; 72(4): 735-42, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12377943

ABSTRACT

Interleukin (IL)-12, especially in the presence of neutralizing anti-IL-4 monoclonal antibodies, primed CD45RO(-) T clones for high CCL3/macrophage-inflammatory protein-1alpha (MIP-1alpha) and CCL4/MIP-1beta levels. In CD4(+) and CD8(+) clones from two patients deficient for IL-12Rbeta1 (IL-12Rbeta1(-/-)), production of CCL3/MIP-1alpha and CCL4/MIP-1beta was defective. CD4(+) clones from two patients deficient for interferon-gamma (IFN-gamma) R1 (IFN-gammaR1(-/-)) produced somewhat decreased CCL4/MIP-1beta levels. IL-12 failed to prime CD4(+) or CD8(+) healthy clones for high CCL5/regulated on activation, normal T expressed and secreted (RANTES) production, although its secretion was impaired in CD4(+) clones from IL-12Rbeta1(-/-) and IFN-gammaR1(-/-) patients. CCR5 surface expression was up-regulated in resting peripheral blood mononuclear cells and CD4(+) clones from both kinds of patients, rendering them more susceptible to CCR5-dependent (R5) HIV-1 infection. Neutralization of IFN-gamma increased CCR5 expression and decreased CC-chemokine secretion by CD4(+) clones from healthy and IL-12Rbeta1(-/-) individuals, suggesting an IFN-gamma-dependent control of CCR5 expression. These data provide the first documented analysis of chemokine secretion and chemokine receptor expression on T cells from IL-12 and IFN-gamma receptor-deficient patients and dissect the role of IL-12 and IFN-gamma on inducing inflammatory chemokine secretion and down-regulating CCR5 expression in human T cells.


Subject(s)
Chemokine CCL5/metabolism , Interferon-gamma/immunology , Interleukin-12/immunology , Macrophage Inflammatory Proteins/metabolism , Receptors, CCR5/biosynthesis , CD4 Antigens , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Cells, Cultured , Chemokine CCL3 , Chemokine CCL4 , Chemokines, CC/metabolism , Down-Regulation , Gene Expression , HIV Infections/blood , HIV Infections/immunology , HIV-1/immunology , HIV-1/physiology , Humans , Interferon-gamma/metabolism , Interleukin-12/pharmacology , Interleukin-4/metabolism , Interleukin-4/pharmacology , Leukocyte Common Antigens , Receptors, Interferon/immunology , Receptors, Interleukin/immunology , Receptors, Interleukin-12 , Virus Replication , Interferon gamma Receptor
2.
Eur J Immunol ; 32(3): 693-700, 2002 03.
Article in English | MEDLINE | ID: mdl-11857344

ABSTRACT

Phytohemagglutinin (PHA)-derived T lymphoblasts or T cell clones from patients genetically deficient in IL-12R beta 1 (IL-12R beta 1(-/-)) or IFN-gamma R1 (IFN-gamma R1(-/-)) produced two- to threefold reduced IFN-gamma levels compared to the corresponding cells from healthy individuals after anti-CD3 and PMA stimulation. Moderate IFN-gamma production was observed in PHA-derived T lymphoblasts or T cell clones derived from healthy subjects in the presence of anti-IFN-gamma R1 or anti-IL-12 mAb, whereas it was negligible in the presence of both mAb. However, when anti-IFN-gamma R1 and/or anti-IL-12 mAb were added during restimulation, the cells produced normal levels of IFN-gamma, indicating that both IFN-gamma and IL-12 had an effect on the priming phase. Moderate production of IFN-gamma was partially enhanced only in IFN-gamma R1(-/-) T cell clones generated in the presence of IL-12, but was almost completely abolished when IL-12R beta 1(-/-) and IFN-gamma R1(-/-) T cell clones were generated in the presence of anti-IFN-gamma R1 or anti-IL-12 mAb, respectively. IL-4 production was enhanced in T cell clones from IL-12R beta 1(-/-),but not from IFN-gamma R1(-/-) patients, whereas IL-10 and IL-2 production did not differ significantly in polyclonal T cells or clones from healthy and deficient individuals. These results indicate that IL-12R beta 1- and IFN-gamma R1-dependent signals co-ordinately regulate IFN-gamma, but not IL-2 and IL-10 production, whereas only IL-12 negatively controls IL-4 production by in vitro-generated T cell clones. Thus, although IL-12 and IFN-gamma signals are each sufficient for moderate production of IFN-gamma by human T cells, both are needed for optimal IFN-gamma production, and in the absence of both IFN-gamma production is completely abrogated.


Subject(s)
Interferon-gamma/biosynthesis , Interferon-gamma/pharmacology , Interleukin-12/physiology , Receptors, Interferon/physiology , Receptors, Interleukin/physiology , T-Lymphocytes/drug effects , Antibodies, Monoclonal/pharmacology , Cells, Cultured , Clone Cells/drug effects , Clone Cells/metabolism , Codon, Nonsense , Gene Expression Regulation/drug effects , Humans , Interferon-gamma/genetics , Interleukin-10/biosynthesis , Interleukin-10/genetics , Interleukin-12/genetics , Interleukin-12/immunology , Interleukin-12/pharmacology , Interleukin-4/biosynthesis , Interleukin-4/genetics , Lymphocyte Activation/drug effects , Phytohemagglutinins/pharmacology , Receptors, Interferon/deficiency , Receptors, Interferon/drug effects , Receptors, Interferon/genetics , Receptors, Interleukin/deficiency , Receptors, Interleukin/drug effects , Receptors, Interleukin/genetics , Receptors, Interleukin-12 , Recombinant Fusion Proteins/pharmacology , Recombinant Proteins , Sequence Deletion , Signal Transduction , T-Lymphocytes/metabolism , Tetradecanoylphorbol Acetate/pharmacology , Interferon gamma Receptor
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