Selective loss of type I interferon-induced STAT4 activation caused by a minisatellite insertion in mouse Stat2

Abstract

The use of murine systems to model pathogen-induced human diseases presumes that general immune mechanisms between these species are conserved. One important immunoregulatory mechanism involves linkage of innate and adaptive immunity to direct the development of T helper subsets, for example toward subset 1 (TH1) development through STAT4 activation. In analyzing type I interferon signaling, we uncovered a difference between murine and human cells which may affect how these two species control linkage between innate and adaptive immunity. We show that in humans, type I interferons induce TH1 development and can activate STAT4 by recruitment to the IFN-alpha receptor complex specifically via the carboxy-terminus of STAT2. However, the mouse Stat2 gene harbors a minisatellite insertion that has altered the carboxy-terminus and selectively disrupted its capacity to activate STAT4, but not other STATs. This defect in murine Stat2 suggests that the signals leading to STAT4 activation and TH1 development in CD4+ T cells are different between mice and humans.

Pre-assembly of STAT4 with the human IFN-α/β receptor-2 subunit is mediated by the STAT4 N-domain

“…Here, IFN-α/β-induced STAT4 tyrosine phosphorylation was found to be dependent upon the presence of human STAT2 (Farrar et al, 2000b). Unlike other STAT family members, STAT2 is highly divergent between mouse and human, and this dissimilarity is particularly striking within the COOH-terminal transactivation domain (Farrar et al, 2000a;Park et al, 1999;Paulson et al, 1999). The sequence divergence in STAT2 is functionally relevant because expression of the murine STAT2 molecule failed to restore IFN-α/β-dependent STAT4 phosphorylation in human STAT2-deficient cells (Farrar et al, 2000a).…”

“…Our previous studies demonstrated that although the human STAT2 C-terminus was required to promote IFN-α-dependent STAT4 activation in human fibroblasts (Farrar et al, 2000a), it was not sufficient to restore this pathway when expressed in murine T cells (Persky et al, 2005). This finding predicts that additional species-specific components of the IFNAR complex regulate STAT4 tyrosine phosphorylation.…”

“…In human CD4 + T cells, IFN-α/ β promotes STAT4 activation (Cho et al, 1996;Farrar et al, 2000b;Rogge et al, 1998) and can drive acute IFN-γ secretion in response to IFN-α/β + IL-18 stimulation (Brinkmann et al, 1993;Matikainen et al, 2001;Parronchi et al, 1992;Sareneva et al, 2000;Sareneva et al, 1998). In murine CD4 + T cells, IFN-α/β is inefficient at promoting STAT4 activation (Berenson et al, 2004;Farrar and Murphy, 2000;Farrar et al, 2000a;Farrar et al, 2000b;Persky et al, 2005;Rogge et al, 1998;Szabo et al, 1997), and as a consequence, murine CD4 + T cells fail to differentiate to Th1 cells and do not secrete IFN-γ in response to IFN-α/ β + IL-18 in vitro (Berenson et al, 2004;Persky et al, 2005;Rogge et al, 1998;Wenner et al, 1996).…”

“…Unlike other STAT family members, STAT2 is highly divergent between mouse and human, and this dissimilarity is particularly striking within the COOH-terminal transactivation domain (Farrar et al, 2000a;Park et al, 1999;Paulson et al, 1999). The sequence divergence in STAT2 is functionally relevant because expression of the murine STAT2 molecule failed to restore IFN-α/β-dependent STAT4 phosphorylation in human STAT2-deficient cells (Farrar et al, 2000a). However, expression of a chimeric murine/human STAT2 molecule, in which the COOH-domain was replaced with the human sequence, restored IFN-α/β-dependent STAT4 activation in STAT2-deficient human fibroblasts.…”

“…However, expression of a chimeric murine/human STAT2 molecule, in which the COOH-domain was replaced with the human sequence, restored IFN-α/β-dependent STAT4 activation in STAT2-deficient human fibroblasts. Based on these studies, it was proposed that the human STAT2 COOH-terminus was a critical species-specific component of the human IFNAR complex that was necessary for IFN-α/β-dependent STAT4 tyrosine phosphorylation Farrar et al, 2000a). This finding was followed by the construction of a knockin mouse that expressed a chimeric murine/human (m/h) Stat2 gene in place of the wild-type murine Stat2 (Persky et al, 2005).…”