Immune Response in Stat 2 Knockout Mice genes through members of the g activation site ( GAS )

genes through members of the g activation site (GAS) Christopher Park,* Suzanne Li,† family of enhancers. GAS-driven genes including IRF-1, Edward Cha,* and Christian Schindler*‡ CIITA (an activator MHC class II), IGTP, MIG, and IP-10 *Departments of Microbiology and Medicine (Decker et al., 1997; Taylor et al., 2000). Consistent with Columbia University these observations, Stat1 knockout mice are defective †Department of Cell Biology in their response to both type I and type II IFNs (Durbin Memorial Sloan Kettering Cancer Institute et al., 1996; Meraz et al., 1996). Thus, Stat2, an uncharacNew York, New York 10021 teristic member of the STAT family (Park et al., 1999), is unique to the biological response to type I IFNs. Receptor gene targeting studies have provided imporSummary tant insight into the distinct biological responses to type I and II IFNs. Specifically, type I IFN receptor a chain Type I IFNs induce gene expression through Stat1 and (IFNAR1) null mice are exquisitely sensitive to infection Stat2, which can in turn associate either to form Stat1 with vesicular stomatitis virus (VSV), semliki forest virus homodimers or the transcription factor ISGF-3. Stat1 (SFV), vaccinia virus (VV), and lymphocytic choriomeninhomodimers also transduce signals for IFN-g. To exgitis virus (LCMV) but not to intracellular pathogens plore the unique properties of Stat2 and ISGF-3 in type (Müller et al., 1994). In contrast, IFN-g and IFN-g receptor I IFN signaling, its gene was targeted for deletion. null mice are defective in their response to VV and LCMV Stat2 null mice exhibit a number of defects in immune but not VSV and SFV (Dalton et al., 1993; Huang et al., response. This includes an increased susceptibility to 1993; Lu et al., 1998). These mice are also uniquely viral infection and the loss of a type I IFN autocrine/ sensitive to infection with obligate intracellular pathoparacrine loop, which in turn regulates several aspects gens and exhibit notable perturbations in cellular imof immune response. Intriguingly, Stat2-deficient fimunity. broblasts exhibit a more significant defect in their reAlthough type I IFNs are well recognized for their role sponse to type I IFNs than macrophages, highlighting in promoting innate antiviral immunity, numerous studtissue-specific differences in the response to this famies have hinted at a more pervasive role in immune ily of ligands. response (Biron, 1998). Recent studies have determined that a circulating dendritic cell precursor secretes large Introduction quantities of type I IFNs in response to infectious stimuli (Siegal et al., 1999). Type I IFNs have also recently been Type I interferons (IFNs) mediate potent antiviral and implicated in promoting the survival of memory T cells, antiproliferative activities on target cells through the acespecially from the CD8 lineage (Tough et al., 1996; tivation of new genes. Characterization of their ability Marrack et al., 1999). This activity contrasts the supto induce these genes led to the elucidation of the JAKpressive effects ascribed to type I IFNs on earlier events STAT signaling pathway, where Janus kinases (JAKs) in lymphopoiesis (Binder et al., 1997; Lin et al., 1998). are receptor-associated tyrosine kinases and signal The recent identification of limitin, a stromally secreted transducers and activators of transcription (STATs) are type I IFN that antagonizes lymphopoiesis, further implithe transcription factors they activate. Subsequent studcates type I IFNs in the regulation of lymphoid developies have determined that most other members of the ment (Oritani et al., 2000). cytokine family transduce vital signals through this paraType I IFNs have also been shown to function through digm (reviewed in Ihle, 1995; Darnell, 1997; Schindler an autocrine loop. Initial studies highlighted the ability and Strehlow, 2000). of type I IFNs to antagonize the growth of several tumor Type I IFN (e.g., IFN-a/b) signaling entails the rapid lines through this loop (Resnitzky et al., 1986; Mattei et receptor-dependent activation of Stat1 and Stat2. Once al., 1994; Kawabata et al., 1997). Subsequent biochemiactivated, these two STATs can either heterodimerize, cal and genetic studies have provided further and comassociate with the DNA binding protein IRF-9 (p48) and pelling evidence that this type I IFN autocrine loop is form ISGF-3 (IFN-stimulated gene factor-3), or they can critical for the robust secretion of type I IFNs in response form Stat1 homodimers (Darnell, 1997; Schindler and to viral infection and the antiviral activity of IFN-g (ErStrehlow, 2000). ISGF-3 promotes the activation of landsson et al., 1998; Wathelet et al., 1998; Takaoka et genes through the IFN-stimulated response element al., 2000). This may reflect the role of “early” type I IFNs (ISRE). ISRE-driven genes include Ly-6C, the doubleas components of an autocrine loop that promotes the stranded RNA kinase (PKR), 29 to 59 oligoadenylate synrobust secretion of “late” type I IFNs (Erlandsson et al., thase (OAS), MX, and potentially MHC class I (Bothwell 1998; Marie et al., 1998; Sato et al., 1998; Takaoka et et al., 1988; Johnson and Pober, 1994; Stark et al., 1998; al., 2000). Lee et al., 1999). Stat1 homodimers, which also play a To address the unique properties of Stat2 in IFN signalcritical role in transducing signals for IFN-g (Durbin et ing, the Stat2 gene has been targeted for deletion by al., 1996; Meraz et al., 1996), promote the activation of homologous recombination. As anticipated, Stat2 knockout mice are unresponsive to type I IFNs and exquisitely sensitive to viral infection. However, they also exhibit a ‡ To whom correspondence should be addressed (e-mail: cws4@