The costimulatory effect of IL-18 on the induction of antigen-specific IFN-gamma production by resting T cells is IL-12 dependent and is mediated by up-regulation of the IL-12 receptor beta2 subunit

Eur J Immunol. 2000 Apr;30(4):1113-9. doi: 10.1002/(SICI)1521-4141(200004)30:4<1113::AID-IMMU1113>3.0.CO;2-P.


IL-18 was originally described as a cytokine which induced IFN-gamma production by established Th1 cells in an IL-12-independent manner. However, subsequent studies demonstrated that exogenous IL-18 in the absence of IL-12 failed to drive Th1 differentiation of naive cells and induced IFN-gamma from established Th1 cells only in combination with IL-12. We have examined the role of endogenous IL-18 in controlling Th1 lineage commitment. When naive TCR-transgenic T cells were stimulated with antigen, anti-IL-18 antibodies resulted in partial inhibition of IFN-gamma production, but did not inhibit Th1 differentiation. To distinguish whether the inhibitory effect of anti-IL-18 antibodies was mediated directly by blocking IFN-gamma production or indirectly by blocking IL-12Rbeta2 up-regulation, naive T cells from IL-12 - / - mice were stimulated with anti-CD3 and IL-18. These cells failed to produce IFN-gamma, but markedly up-regulated IL-12Rbeta2 expression. We propose that the major effect of IL-18 on Th1 development is mediated by up-regulation of IL-12Rbeta2 expression, thereby enhancing IL-12-mediated signaling. The enhancement of IL-12Rbeta2 expression by IL-18 may be particularly important for the differentiation of foreign antigen- or autoantigen-specific Th1 cells when the stimulatory concentration of IL-12 in the microenvironment is just below the threshold required for Th1 development.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies / immunology
  • Antibodies / pharmacology
  • Autoimmunity / drug effects
  • Autoimmunity / immunology
  • CD3 Complex / immunology
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Gene Deletion
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / biosynthesis*
  • Interleukin-12 / antagonists & inhibitors
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology
  • Interleukin-12 / pharmacology*
  • Interleukin-18 / antagonists & inhibitors
  • Interleukin-18 / immunology
  • Interleukin-18 / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Myelin Basic Protein / immunology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Interleukin / chemistry
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism*
  • Receptors, Interleukin-12
  • Signal Transduction / drug effects
  • Th1 Cells / cytology
  • Th1 Cells / drug effects
  • Th1 Cells / immunology
  • Th1 Cells / metabolism*
  • Up-Regulation / drug effects


  • Antibodies
  • CD3 Complex
  • Il12rb2 protein, mouse
  • Interleukin-18
  • Myelin Basic Protein
  • RNA, Messenger
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • Interleukin-12
  • Interferon-gamma