title: 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.
abstract: 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.
authors.affiliation: Department of Immunohematology and Blood Transfusion, 2300 RC Leiden University Medical Center (LUMC), 2300 RC, Leiden, The Netherlands.
authors.forename: C E
authors.initials: CE
authors.lastname: Verhagen
authors.lastname: de Boer T
authors.forename: H H
authors.initials: HH
authors.lastname: Smits
authors.forename: F A
authors.initials: FA
authors.lastname: Verreck
authors.forename: E A
authors.initials: EA
authors.lastname: Wierenga
authors.forename: M
authors.initials: M
authors.lastname: Kurimoto
authors.forename: D A
authors.initials: DA
authors.lastname: Lammas
authors.forename: D S
authors.initials: DS
authors.lastname: Kumararatne
authors.forename: O
authors.initials: O
authors.lastname: Sanal
authors.forename: F P
authors.initials: FP
authors.lastname: Kroon
authors.lastname: van Dissel JT
authors.forename: F
authors.initials: F
authors.lastname: Sinigaglia
authors.forename: T H
authors.initials: TH
authors.lastname: Ottenhoff
mesh_terms: D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007223:Infant; D039503:Integrin alpha6; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000276:immunology*; D020382:Interleukin-18 / Q000378:metabolism; D053727:Interleukin-18 Receptor alpha Subunit; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D015270:Mycobacterium avium-intracellulare Infection / Q000276:immunology*; D009570:Nitriles / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; D050797:STAT4 Transcription Factor; D012480:Salmonella Infections / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D002070:Butadienes; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C508438:IL12RB1 protein, human; C508572:IL18R1 protein, human; D007093:Imidazoles; D039503:Integrin alpha6; D016898:Interferon-alpha; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D009570:Nitriles; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D017471:Receptors, Interferon; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; C113580:U 0126; D053633:Receptor, Interferon alpha-beta; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; C093642:SB 203580