Home LiteratureArticle Details
PMID: 10952721 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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.

The Journal of experimental medicine ·Vol. 192 ·No. 4 ·2000-08-21 ·Pages 517-28

Verhagen CE, de Boer T, Smits HH, Verreck FA, Wierenga EA, Kurimoto M, Lammas DA, Kumararatne DS, Sanal O, Kroon FP, van Dissel JT, Sinigaglia F, Ottenhoff TH

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.

MeSH Terms
Adolescent Adult Antigens, CD/metabolism Butadienes/pharmacology Child Child, Preschool DNA-Binding Proteins/genetics,metabolism Enzyme Inhibitors/pharmacology Female Humans Imidazoles/pharmacology Infant Integrin alpha6 Interferon-alpha/metabolism Interferon-gamma/biosynthesis Interleukin-12/immunology Interleukin-18/metabolism Interleukin-18 Receptor alpha Subunit Interleukin-4/metabolism Male Mycobacterium avium-intracellulare Infection/immunology Nitriles/pharmacology Proto-Oncogene Proteins c-myc/genetics,metabolism Pyridines/pharmacology Receptor, Interferon alpha-beta Receptors, Interferon/metabolism Receptors, Interleukin/genetics,metabolism,physiology Receptors, Interleukin-12 Receptors, Interleukin-18 STAT4 Transcription Factor Salmonella Infections/immunology Signal Transduction T-Lymphocytes/immunology Th1 Cells/immunology Trans-Activators/genetics,metabolism
Chemicals
Antigens, CD Butadienes DNA-Binding Proteins Enzyme Inhibitors IL12RB1 protein, human IL18R1 protein, human Imidazoles Integrin alpha6 Interferon-alpha Interleukin-18 Interleukin-18 Receptor alpha Subunit Nitriles Proto-Oncogene Proteins c-myc Pyridines Receptors, Interferon Receptors, Interleukin Receptors, Interleukin-12 Receptors, Interleukin-18 STAT4 Transcription Factor STAT4 protein, human Trans-Activators U 0126 Receptor, Interferon alpha-beta Interleukin-12 Interleukin-4 Interferon-gamma SB 203580
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Verhagen C E
Department of Immunohematology and Blood Transfusion, 2300 RC Leiden University Medical Center (LUMC), 2300 RC, Leiden, The Netherlands.
de Boer T
Smits H H
Verreck F A
Wierenga E A
Kurimoto M
Lammas D A
Kumararatne D S
Sanal O
Kroon F P
van Dissel JT
Sinigaglia F
Ottenhoff T H
References (48)
48 references, click to expand
  1. Signals involved in T cell activation. T cell proliferation induced through the synergistic action of anti-CD28 and anti-CD2 monoclonal antibodies.
    Eur J Immunol. 1988 Jan;18(1):167-72 PMID: 3126073
  2. Reversal reaction in borderline leprosy is associated with a polarized shift to type 1-like Mycobacterium leprae T cell reactivity in lesional skin: a follow-up study.
    J Immunol. 1997 Nov 1;159(9):4474-83 PMID: 9379047
  3. Allergen- and bacterial antigen-specific T-cell clones established from atopic donors show a different profile of cytokine production.
    Proc Natl Acad Sci U S A. 1991 May 15;88(10):4538-42 PMID: 1827920
  4. Selection of a human T helper type 1-like T cell subset by mycobacteria.
    J Exp Med. 1991 Sep 1;174(3):583-92 PMID: 1831489
  5. Characterization of the promoter of the human gene encoding the high-affinity IgG receptor: transcriptional induction by gamma-interferon is mediated through common DNA response elements.
    Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11305-9 PMID: 1837149
  6. Functional subsets of allergen-reactive human CD4+ T cells.
    Immunol Today. 1991 Nov;12(11):392-5 PMID: 1686170
  7. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages.
    Science. 1993 Apr 23;260(5107):547-9 PMID: 8097338
  8. Interleukin-12 induces tyrosine phosphorylation and activation of 44-kD mitogen-activated protein kinase in human T cells.
    Blood. 1994 Jan 1;83(1):184-90 PMID: 7903874
  9. Expression cloning of a human IL-12 receptor component. A new member of the cytokine receptor superfamily with strong homology to gp130.
    J Immunol. 1994 Jul 1;153(1):128-36 PMID: 7911493
  10. Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12.
    J Exp Med. 1995 Jan 1;181(1):399-404 PMID: 7528775
  11. Developmental commitment to the Th2 lineage by extinction of IL-12 signaling.
    Immunity. 1995 Jun;2(6):665-75 PMID: 7796298
  12. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity.
    Annu Rev Immunol. 1995;13:251-76 PMID: 7612223
  13. Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes.
    Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7307-11 PMID: 7638186
  14. A synthetic inhibitor of the mitogen-activated protein kinase cascade.
    Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686-9 PMID: 7644477
  15. Interferon-gamma-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-gamma production.
    Eur J Immunol. 1996 Jul;26(7):1647-51 PMID: 8766574
  16. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells.
    Nature. 1996 Jul 11;382(6587):171-4 PMID: 8700208
  17. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice.
    Nature. 1996 Jul 11;382(6587):174-7 PMID: 8700209
  18. Functional diversity of helper T lymphocytes.
    Nature. 1996 Oct 31;383(6603):787-93 PMID: 8893001
  19. Lack of IL-12 signaling in human allergen-specific Th2 cells.
    J Immunol. 1996 Nov 15;157(10):4316-21 PMID: 8906805
  20. A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits.
    Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14002-7 PMID: 8943050
  21. Altered interleukin-12 responsiveness in Th1 and Th2 cells is associated with the differential activation of STAT5 and STAT1.
    Blood. 1998 Feb 15;91(4):1341-54 PMID: 9454765
  22. Mice lacking IL-12 develop polarized Th1 cells during viral infection.
    J Immunol. 1998 Apr 15;160(8):3958-64 PMID: 9558103
  23. Alloantigen-reactive Th1 development in IL-12-deficient mice.
    J Immunol. 1998 Feb 1;160(3):1132-8 PMID: 9570526
  24. Interferon-gamma expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway.
    EMBO J. 1998 May 15;17(10):2817-29 PMID: 9582275
  25. Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency.
    Science. 1998 May 29;280(5368):1432-5 PMID: 9603732
  26. Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients.
    Science. 1998 May 29;280(5368):1435-8 PMID: 9603733
  27. Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection.
    J Clin Invest. 1998 Jun 1;101(11):2364-9 PMID: 9616207
  28. Influenza A virus-induced IFN-alpha/beta and IL-18 synergistically enhance IFN-gamma gene expression in human T cells.
    J Immunol. 1998 Jun 15;160(12):6032-8 PMID: 9637519
  29. Interleukin-12 induces tyrosine phosphorylation of an 85-kDa protein associated with the interleukin-12 receptor beta 1 subunit.
    Cell Immunol. 1998 May 25;186(1):39-44 PMID: 9637763
  30. Identification of a novel inhibitor of mitogen-activated protein kinase kinase.
    J Biol Chem. 1998 Jul 17;273(29):18623-32 PMID: 9660836
  31. Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells.
    J Exp Med. 1998 Oct 19;188(8):1485-92 PMID: 9782125
  32. Constitutive and induced IL-18 receptor expression by various peripheral blood cell subsets as determined by anti-hIL-18R monoclonal antibody.
    Cell Immunol. 1998 Nov 1;189(2):135-43 PMID: 9790727
  33. Novel human immunodeficiencies reveal the essential role of type-I cytokines in immunity to intracellular bacteria.
    Immunol Today. 1998 Nov;19(11):491-4 PMID: 9818540
  34. Requirement for distinct Janus kinases and STAT proteins in T cell proliferation versus IFN-gamma production following IL-12 stimulation.
    J Immunol. 1998 Dec 1;161(11):5893-900 PMID: 9834069
  35. Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection.
    J Clin Invest. 1998 Dec 15;102(12):2035-40 PMID: 9854038
  36. The role of Stat4 in species-specific regulation of Th cell development by type I IFNs.
    J Immunol. 1998 Dec 15;161(12):6567-74 PMID: 9862683
  37. Antibodies to the IL-12 receptor beta 2 chain mark human Th1 but not Th2 cells in vitro and in vivo.
    J Immunol. 1999 Apr 1;162(7):3926-32 PMID: 10201911
  38. The functional synergy between IL-12 and IL-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of STAT serine phosphorylation.
    J Immunol. 1999 Apr 15;162(8):4472-81 PMID: 10201984
  39. IL-18 promotes type 1 cytokine production from NK cells and T cells in human intracellular infection.
    J Immunol. 1999 May 15;162(10):6114-21 PMID: 10229854
  40. Upregulation of integrin alpha6/beta1 and chemokine receptor CCR1 by interleukin-12 promotes the migration of human type 1 helper T cells.
    Blood. 1999 Nov 1;94(9):2981-9 PMID: 10556180
  41. Regulation of the IL-12/IL-12R axis: a critical step in T-helper cell differentiation and effector function.
    Immunol Rev. 1999 Aug;170:65-72 PMID: 10566142
  42. Mycobacterium leprae-specific protein antigens defined by cloned human helper T cells.
    Nature. 1986 Jan 2-8;319(6048):66-8 PMID: 2417123
  43. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection.
    N Engl J Med. 1996 Dec 26;335(26):1941-9 PMID: 8960473
  44. IL-12-deficient mice are defective but not devoid of type 1 cytokine responses.
    Ann N Y Acad Sci. 1996 Oct 31;795:60-70 PMID: 8958917
  45. Differential associations between the cytoplasmic regions of the interleukin-12 receptor subunits beta1 and beta2 and JAK kinases.
    J Biol Chem. 1997 Feb 28;272(9):6073-7 PMID: 9038232
  46. Selective expression of an interleukin-12 receptor component by human T helper 1 cells.
    J Exp Med. 1997 Mar 3;185(5):825-31 PMID: 9120388
  47. Structural and functional aspects of the IL-12 receptor complex.
    Chem Immunol. 1997;68:23-37 PMID: 9329214
  48. IL-4 directs the development of Th2-like helper effectors.
    J Immunol. 1990 Dec 1;145(11):3796-806 PMID: 2147202
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.192.4.517
Published
2000-08-21
Pages
517-28
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193232
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.192.4.517 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2