IL-2 receptor blockade inhibits late, but not early, IFN-gamma and CD40 ligand expression in human T cells: disruption of both IL-12-dependent and -independent pathways of IFN-gamma production

• Published in: The Journal of immunology (1950) 2002-09, Vol.169 (5), p.2736-2746
• Main Authors: McDyer, John F, Li, Zhuqing, John, Susan, Yu, Xiang, Wu, Chang-You, Ragheb, Jack A
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; CD28 Antigens - pharmacology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD40 Ligand - biosynthesis; CD40 Ligand - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Membrane - immunology; Cell Membrane - metabolism; Cell Separation; Cells, Cultured - immunology; Cells, Cultured - metabolism; Centrifugation, Density Gradient; Cytokines - biosynthesis; Daclizumab; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; Humans; Immunoglobulin G - pharmacology; Immunosuppressive Agents - pharmacology; Interferon-gamma - antagonists & inhibitors; Interferon-gamma - biosynthesis; Interleukin-12 - antagonists & inhibitors; Interleukin-12 - biosynthesis; Interleukin-12 - pharmacology; Interleukin-12 - physiology; Interleukin-2 - physiology; Interleukin-2 Receptor alpha Subunit; Janus Kinase 3; Leukocytes, Mononuclear - enzymology; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; Lymphocyte Activation - immunology; Milk Proteins; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Receptors, Interleukin - biosynthesis; Receptors, Interleukin - immunology; Receptors, Interleukin-12; Receptors, Interleukin-2 - antagonists & inhibitors; Receptors, Interleukin-2 - immunology; Receptors, Interleukin-2 - physiology; Signal Transduction - immunology; STAT5 Transcription Factor; T-Lymphocyte Subsets - enzymology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Th1 Cells - immunology; Th1 Cells - metabolism; Th2 Cells - immunology; Th2 Cells - metabolism; Time Factors; Trans-Activators - antagonists & inhibitors; Trans-Activators - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.169.5.2736

mAbs directed against the alpha-chain (Tac/CD25) of the IL-2R are an emerging therapy in both transplantation and autoimmune disease. However, the mechanisms underlying their therapeutic efficacy have not been fully elucidated. Therefore, we examined the effect of IL-2R blockade on Th1 and Th2 cytokine production from human PBMC. Addition of a humanized anti-Tac Ab (HAT) to activated PBMC cultures inhibited IFN-gamma production from CD4 and CD8 T cells by 80-90%. HAT partially inhibited production of TNF-alpha and completely inhibited production of IL-4, IL-5, and IL-10. Furthermore, IL-12, a central regulatory cytokine that induces IFN-gamma, was undetectable in treated cultures. As T cell-dependent induction of IL-12 is regulated via CD40/CD40 ligand (CD40L) interactions, we examined the effect of HAT on CD40L expression. We found CD40L expression to be biphasic with an early (6 h) peak that is CD28/IL-2-independent, but a later peak (48 h) being CD28/IL-2-dependent and inhibited by HAT. Similarly, IFN-gamma production at 6 h was CD28/IL-2-independent but CD28/IL-2-dependent and inhibited by HAT at 48 h. Nonetheless, addition of rCD40L or exogenous IL-12 to HAT-treated cultures could not restore IFN-gamma production. The IFN-gamma deficit in such cultures appears to be due to a direct inhibition by HAT of IL-12-independent IFN-gamma production from T cells rather than altered expression of either the IL-12Rbeta1 or IL-12Rbeta2 chains. These data demonstrate that IL-2 plays a critical role in the regulation of Th1 and Th2 responses and impacts both IL-12-dependent and -independent IFN-gamma production.