IFN-γ and IL-12 differentially regulate CC-chemokine secretion and CCR5 expression in human T lymphocytes

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-1α (MIP-1α) and CCL4/MIP-1β levels. In CD4+ and CD8+ clones from two patients deficient for IL-12Rβ1 (IL-12Rβ1−/−), production of CCL3/MIP-1α and CCL4/MIP-1β was defective. CD4+ clones from two patients deficient for interferon-γ (IFN-γ) R1 (IFN-γR1−/−) produced somewhat decreased CCL4/MIP-1β 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-12Rβ1−/− and IFN-γR1−/− 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-γ increased CCR5 expression and decreased CC-chemokine secretion by CD4+ clones from healthy and IL-12Rβ1−/− individuals, suggesting an IFN-γ-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-γ receptor-deficient patients and dissect the role of IL-12 and IFN-γ on inducing inflammatory chemokine secretion and down-regulating CCR5 expression in human T cells.