Requirement for both IL‐12 and IFN‐γ signaling pathways in optimal IFN‐γ production by human T cells

• Published in: European journal of immunology 2002-03, Vol.32 (3), p.693-700
• Main Authors: Losana, Giuliana, Rigamonti, Laura, Borghi, Igor, Assenzio, Barbara, Ariotti, Silvia, Jouanguy, Emmanuelle, Altare, Frederic, Forni, Guido, Casanova, Jean‐Laurent, Novelli, Francesco
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - pharmacology; Cells, Cultured; Clone Cells - drug effects; Clone Cells - metabolism; Codon, Nonsense; Cytokine; Cytokine receptor; g-Interferon; Gene Expression Regulation - drug effects; Human; Humans; Interferon gamma Receptor; Interferon-gamma - biosynthesis; Interferon-gamma - genetics; Interferon-gamma - pharmacology; Interleukin-10 - biosynthesis; Interleukin-10 - genetics; Interleukin-12 - genetics; Interleukin-12 - immunology; Interleukin-12 - pharmacology; Interleukin-12 - physiology; Interleukin-4 - biosynthesis; Interleukin-4 - genetics; Lymphocyte Activation - drug effects; Phytohemagglutinins - pharmacology; Receptors, Interferon - deficiency; Receptors, Interferon - drug effects; Receptors, Interferon - genetics; Receptors, Interferon - physiology; Receptors, Interleukin - deficiency; Receptors, Interleukin - drug effects; Receptors, Interleukin - genetics; Receptors, Interleukin - physiology; Receptors, Interleukin-12; Recombinant Fusion Proteins - pharmacology; Recombinant Proteins; Sequence Deletion; Signal Transduction; T lymphocyte; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Tetradecanoylphorbol Acetate - pharmacology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/1521-4141(200203)32:3<693::AID-IMMU693>3.0.CO;2-Q

Phytohemagglutinin (PHA)‐derived T lymphoblasts or T cell clones from patients genetically deficient in IL‐12Rβ1 (IL‐12Rβ1–/–) or IFN‐γR1 (IFN‐γR1–/–) produced two‐ to threefold reduced IFN‐γ levels compared to the corresponding cells from healthy individuals after anti‐CD3 and PMA stimulation. Moderate IFN‐γ production was observed in PHA‐derived T lymphoblasts or T cell clones derived from healthy subjects in the presence of anti‐IFN‐γR1 or anti‐IL‐12 mAb, whereas it was negligible in the presence of both mAb. However, when anti‐IFN‐γR1 and/or anti‐IL‐12 mAb were added during restimulation, the cells produced normal levels of IFN‐γ, indicating that both IFN‐γ and IL‐12 had an effect on the priming phase. Moderate production of IFN‐γ was partially enhanced only in IFN‐γR1–/– T cell clones generated in the presence of IL‐12, but was almost completely abolished when IL‐12Rβ1–/– and IFN‐γR1–/– T cell clones were generated in the presence of anti‐IFN‐γR1 or anti‐IL‐12 mAb, respectively. IL‐4 production was enhanced in T cell clones from IL‐12Rβ1–/–,but not from IFN‐γR1–/– 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‐12Rβ1‐ and IFN‐γR1‐dependent signals co‐ordinately regulate IFN‐γ, 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‐γ signals are each sufficient for moderate production of IFN‐γ by human T cells, both are needed for optimal IFN‐γ production, and in the absence of both IFN‐γ production is completely abrogated.