Interleukin 12-Augmented T Cell Proliferation of Peripheral Blood Mononuclear Cells from HIV-Seropositive Individuals Is Associated with Interleukin 12 Receptor β2 Upregulation

Abstract

Interleukin 12 (IL-12) production is believed to be impaired in individuals with HIV infection and this impairment manifests early in disease, when the CD4⁺ cell counts are within normal values. The reduced antigen-specific and mitogen-stimulated T cell-proliferative responses that occur in HIV infection can be corrected by the addition of recombinant human interleukin 12 (rhIL-12). As the IL-12 receptor (IL-12R) is central to the IL-12 signaling pathway, we examined whether the augmentation of antigen-specific proliferation of HIV⁺ peripheral blood mononuclear cells (PBMCs) related to altered IL-12R expression. rhIL-12 augmented antigen-specific proliferation of HIV⁺ PBMCs but not of HIV^- PBMCs. Examination of resting PBMCs from HIV⁺ and HIV^- donors showed that neither of these populations expressed IL-12Rβ1 or IL-12Rβ2 chains on their cell surface as detected by flow cytometry. However, examination of mRNA showed that both IL-12Rβ1 and IL-12Rβ2 mRNAs were markedly reduced in HIV⁺ PBMCs when compared with HIV^- PBMCs. After mitogen activation there was an increase in IL-12Rβ1 expression on the cell surface of HIV⁺ and HIV^- PBMCs and this level was not altered by coculture with rhIL-12 or interferon γ (IFN-γ). However, coculture of phytohemagglutinin (PHA)-activated HIV⁺ or HIV^- PBMCs with rhIL-12 (but not IFN-γ) increased IL-12Rβ2 expression on the cell surface of both populations. Examination at the message level showed a correction of IL-12Rβ1 to normal levels with activation that was further enhanced by rhIL-12 coculture for both the HIV⁺ and HIV^- PBMCs. However, although the level of IL-12Rβ2 for the HIV⁺ PBMCs was normalized by PHA, rhIL-12 caused a further augmentation. This information provides a strong link between IL-12R upregulation, and the significant improvement in antigen-specific HIV-proliferative responses seen with the addition of rhIL-12. It also reveals that the dysfunction in IL-12R expression seen in cells from HIV⁺ patients occurs at the transcriptional level. In addition, we provide further evidence that IL-12Rβ1 and IL-12Rβ2 regulation in human PBMCs is independent of IFN-γ.