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.
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.
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
John F
JF
McDyer
Zhuqing
Z
Li
Susan
S
John
Xiang
X
Yu
Chang-You
CY
Wu
Jack A
JA
Ragheb
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000096:biosynthesis* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured / Q000276:immunology / Q000378:metabolism; D002499:Centrifugation, Density Gradient; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077561:Daclizumab; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D007376:Interleukin-2 / Q000502:physiology; D053645:Interleukin-2 Receptor alpha Subunit; D053616:Janus Kinase 3; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008894:Milk Proteins; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000276:immunology; D053707:Receptors, Interleukin-12; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens; D016207:Cytokines; D004268:DNA-Binding Proteins; C508017:IL2RA protein, human; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D008894:Milk Proteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma; D000077561:Daclizumab; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3