Residual type 1 immunity in patients genetically deficient for interleukin 12 receptor beta1 (IL-12Rbeta1): evidence for an IL-12Rbeta1-independent pathway of IL-12 responsiveness in human T cells
| Autor: | C E, Verhagen, de Boer T, H H, Smits, F A, Verreck, E A, Wierenga, M, Kurimoto, D A, Lammas, D S, Kumararatne, O, Sanal, F P, Kroon, van Dissel JT, F, Sinigaglia, T H, Ottenhoff |
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| Rok vydání: | 2000 |
| Předmět: |
Adult
Male Adolescent Pyridines mycobacteria T-Lymphocytes Receptor Interferon alpha-beta Integrin alpha6 interleukin 18 (receptor) Proto-Oncogene Proteins c-myc Th1 Interferon-gamma Antigens CD interferon-γ Nitriles Butadienes Humans Enzyme Inhibitors Child Mycobacterium avium-intracellulare Infection Receptors Interferon Receptors Interleukin-18 Imidazoles Interleukin-18 Receptors Interleukin-12 Infant Interferon-alpha Receptors Interleukin STAT4 Transcription Factor Th1 Cells interleukin 12 (receptor) Interleukin-12 DNA-Binding Proteins Child Preschool Salmonella Infections Trans-Activators Female Original Article Interleukin-4 Interleukin-18 Receptor alpha Subunit Signal Transduction |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 0022-1007 |
| Popis: | Genetic lack of interleukin 12 receptor beta1 (IL-12Rbeta1) surface expression predisposes to severe infections by poorly pathogenic mycobacteria or Salmonella and causes strongly decreased, but not completely abrogated, interferon (IFN)-gamma production. To study IL-12Rbeta1-independent residual IFN-gamma production, we have generated mycobacterium-specific T cell clones (TCCs) from IL-12Rbeta1-deficient individuals. All TCCs displayed a T helper type 1 phenotype and the majority responded to IL-12 by increased IFN-gamma production and proliferative responses upon activation. This response to IL-12 could be further augmented by exogenous IL-18. IL-12Rbeta2 was found to be normally expressed in the absence of IL-12Rbeta1, and could be upregulated by IFN-alpha. Expression of IL-12Rbeta2 alone, however, was insufficient to induce signal transducer and activator of transcription (Stat)4 activation in response to IL-12, whereas IFN-alpha/IFN-alphaR ligation resulted in Stat4 activation in both control and IL-12Rbeta1-deficient cells. IL-12 failed to upregulate cell surface expression of IL-18R, integrin alpha6, and IL-12Rbeta2 on IL-12Rbeta1-deficient cells, whereas this was normal on control cells. IL-12-induced IFN-gamma production in IL-12Rbeta1-deficient T cells could be inhibited by the p38 mitogen-activated protein kinase (MAP) kinase inhibitor SB203580 and the MAP kinase kinase (MEK) 1/2 inhibitor U0126, suggesting involvement of MAP kinases in this alternative, Stat4-independent, IL-12 signaling pathway.Collectively, these results indicate that IL-12 acts as a partial agonist in the absence of IL-12Rbeta1. Moreover, the results reveal the presence of a novel IL-12Rbeta1/Stat4-independent pathway of IL-12 responsiveness in activated human T cells involving MAP kinases. This pathway is likely to play a role in the residual type 1 immunity in IL-12Rbeta1 deficiency. |
| Databáze: | OpenAIRE |
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