Impaired type I IFN-induced Jak/STAT signaling in FA-C cells and abnormal CD4+ Th cell subsets in Fancc-/- mice

J Immunol. 2004 Sep 15;173(6):3863-70. doi: 10.4049/jimmunol.173.6.3863.

Abstract

The Fanconi anemia (FA) group C protein, FANCC, interacts with STAT1 following stimulation with IFN-gamma and is required for proper docking of STAT1 at the IFN-gamma receptor alpha-chain (IFN-gammaRalpha, IFN-gammaR1). Consequently, loss of a functional FANCC results in decreased activation of STAT1 following IFN-gamma stimulation. Because type I IFN receptors influence the function of type II receptors, and vice versa, we conducted experiments designed to determine whether type I IFN-induced activation of other STAT proteins is compromised in FA-C cells and found that activation of STAT 1, 3, and 5 is diminished in type I IFN-stimulated cells bearing Fancc-inactivating mutations. We also determined that the reduced activation of STATs was accompanied by significant reduction of type I IFN-induced tyrosine kinase 2 and Jak1 phosphorylation. Because tyrosine kinase 2 plays a role in differentiation of Th cells, we quantified cytokine secretion from CD4+ cells and in vitro generated CD4+ Th cell subsets from splenocytes of Fancc null mice to that of heterozygous mice and discovered reduced CD4+ IFN-gamma secretion in the Fancc-/- mouse, indicating impaired Th1 differentiation. We suggest that Fancc mutations result in a subtle immunological defect owing to the failure of FANCC to normally support Jak/STAT signaling.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • B-Lymphocyte Subsets / enzymology
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / pathology*
  • Cell Cycle Proteins*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Line, Transformed
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism
  • Fanconi Anemia / enzymology*
  • Fanconi Anemia / genetics
  • Fanconi Anemia / immunology*
  • Fanconi Anemia Complementation Group C Protein
  • Fanconi Anemia Complementation Group Proteins
  • Gene Silencing / immunology
  • Interferon Type I / physiology*
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / biosynthesis
  • Interleukin-6 / physiology
  • Janus Kinase 1
  • Leukemia Inhibitory Factor
  • Mice
  • Mice, Knockout
  • Nuclear Proteins*
  • Phosphorylation
  • Protein Binding / immunology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Protein-Tyrosine Kinases / physiology*
  • Proteins / genetics*
  • Proteins / physiology
  • Receptor, Interferon alpha-beta
  • Receptors, Interferon / biosynthesis
  • Receptors, Interferon / metabolism
  • STAT1 Transcription Factor
  • STAT2 Transcription Factor
  • Signal Transduction / immunology*
  • Spleen / immunology
  • Spleen / pathology
  • TYK2 Kinase
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th1 Cells / pathology
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Fancc protein, mouse
  • Fanconi Anemia Complementation Group C Protein
  • Fanconi Anemia Complementation Group Proteins
  • Interferon Type I
  • Interleukin-6
  • Leukemia Inhibitory Factor
  • Lif protein, mouse
  • Nuclear Proteins
  • Proteins
  • Receptors, Interferon
  • STAT1 Transcription Factor
  • STAT2 Transcription Factor
  • Stat1 protein, mouse
  • Trans-Activators
  • Receptor, Interferon alpha-beta
  • Interferon-gamma
  • Protein-Tyrosine Kinases
  • Jak1 protein, mouse
  • Janus Kinase 1
  • TYK2 Kinase
  • Tyk2 protein, mouse