Control of Leishmania major in the absence of Tyk2 kinase

Eur J Immunol. 2004 Feb;34(2):519-29. doi: 10.1002/eji.200324465.

Abstract

IL-12 is indispensable for the control of many intracellular pathogens, but the components of the signaling pathway that are essential for its function in vivo are incompletely understood. Here, we investigated in the Leishmania major mouse model whether Tyk2 kinase is required for the generation of a protective immune response. Unlike C57BL/6 controls, Tyk2(-/-)mice developed severe skin lesions after infection that frequently ulcerated, but ultimately healed. NK cell cytotoxicity was absent in infected Tyk2(-/-) mice, even after IL-12 pretreatment, which correlated with a STAT4 activation defect. IFN-alpha / beta, which was still able to activate STAT1 in Tyk2(-/-) NK cells, reconstituted their cytotoxic activity, but not their IL-12 responsiveness. The IL-12-induced production of IFN-gamma by NK cells and CD8(+) T cells was strongly suppressed in Tyk2(-/-) mice at day 1 of infection, but partly regained during the late phase of infection. Tyk2(-/-) CD4(+) T cells developed into Th1 cells (although in a delayed fashion) and infected Tyk2(-/-) mice expressed normals levels of inducible NO synthase. Thus, Tyk2 is required for the IL-12 response of NK cells and CD8(+) T cells in L. major-infected mice, but not for the generation of Th1 cells and the ultimate control of the disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Flow Cytometry
  • Host-Parasite Interactions
  • Interferon-Stimulated Gene Factor 3
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-12 / immunology*
  • Killer Cells, Natural / immunology
  • Leishmania major / enzymology*
  • Leishmania major / immunology*
  • Leishmaniasis, Cutaneous / enzymology
  • Leishmaniasis, Cutaneous / immunology*
  • Leishmaniasis, Cutaneous / parasitology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / immunology
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Protein-Tyrosine Kinases*
  • Proteins / genetics
  • Proteins / immunology*
  • RNA / chemistry
  • RNA / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT4 Transcription Factor
  • Signal Transduction
  • TYK2 Kinase
  • Th1 Cells / immunology
  • Trans-Activators / immunology
  • Trans-Activators / metabolism
  • Transcription Factors / immunology
  • Transcription Factors / metabolism

Substances

  • DNA-Binding Proteins
  • Interferon-Stimulated Gene Factor 3
  • Proteins
  • STAT4 Transcription Factor
  • Stat4 protein, mouse
  • Trans-Activators
  • Transcription Factors
  • gamma interferon activation factor
  • Interleukin-12
  • RNA
  • Interferon-gamma
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Protein-Tyrosine Kinases
  • TYK2 Kinase
  • Tyk2 protein, mouse