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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.

Impaired Type I IFN-Induced Jak/STAT Signaling in FA-C Cells and Abnormal CD4+ Th Cell Subsets in Fancc−/− Mice