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

Sara R. Fagerlie, Tara Koretsky, Beverly Torok-Storb, Grover C. Bagby

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    21 Scopus citations

    Abstract

    The Fanconi anemia (FA) group C protein, FANCC, interacts with STAT1 following stimulation with IFN-γ and is required for proper docking of STAT1 at the IFN-γ receptor α-chain (IFN-γRα, IFN-γR1). Consequently, loss of a functional FANCC results in decreased activation of STAT1 following IFN-γ 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-γ 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.

    Original languageEnglish (US)
    Pages (from-to)3863-3870
    Number of pages8
    JournalJournal of Immunology
    Volume173
    Issue number6
    DOIs
    StatePublished - Sep 15 2004

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    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

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