IFN-gamma and IL-12 differentially regulate CC-chemokine secretion and CCR5 expression in human T lymphocytes.
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.
Losana
Giuliana
G
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
Bovolenta
Chiara
C
Rigamonti
Laura
L
Borghi
Igor
I
Altare
Frederic
F
Jouanguy
Emmanuelle
E
Forni
Guido
G
Casanova
Jean-Laurent
JL
Sherry
Barbara
B
Mengozzi
Manuela
M
Trinchieri
Giorgio
G
Poli
Guido
G
Gerosa
Franca
F
Novelli
Francesco
F
D015704:CD4 Antigens; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism*; D019742:Chemokines, CC / Q000378:metabolism; D015536:Down-Regulation; D015870:Gene Expression; D015658:HIV Infections / Q000097:blood / Q000276:immunology; D015497:HIV-1 / Q000276:immunology / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology* / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology; D017493:Leukocyte Common Antigens; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism*; D019713:Receptors, CCR5 / Q000096:biosynthesis*; D017471:Receptors, Interferon / Q000276:immunology; D018123:Receptors, Interleukin / Q000276:immunology; D053707:Receptors, Interleukin-12; D014779:Virus Replication; D000096743:Interferon gamma Receptor
D015704:CD4 Antigens; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D007371:Interferon-gamma; D018664:Interleukin-12; D015847:Interleukin-4; D017493:Leukocyte Common Antigens; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D017471:Receptors, Interferon; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D000096743:Interferon gamma Receptor