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STAT1 is an essential transcription factor regulating interferon (IFN) dependent gene expression and STAT1-deficient humans and mice are highly susceptible to bacterial and viral infections. Alternative splicing of STAT1 results in a full-length STAT1α and a truncated STAT1β isoform, which lacks parts of the C-terminal transactivation domain. We generated STAT1α and STAT1β only expressing mice and could show that STAT1β is not merely a dominant negative factor but is capable of contributing to innate host defence against bacterial infection in vivo , albeit less efficient than STAT1α. Consistently, we found that STAT1α and STAT1β drive distinct transcriptional profiles in response to IFNγ: around half of STAT1-regulated genes were equally well induced by either STAT1α or STAT1β, whereas other target genes showed reduced, delayed or even no induction in the presence of STAT1β only. Phosphorylation and nuclear localisation of STAT1β was prolonged in the absence of STAT1α. This correlated with prolonged binding to target gene promoters but, surprisingly, did not lead to a generally enhanced response as only a small subset of genes showed increased expression at late time points. Phosphorylated STAT1β was not resistant to phosphatases, suggesting that the impaired induction of the negative regulator suppressor of cytokine signalling 1 (SOCS1) by STAT1β causes its more persistent activation. In contrast to IFNγ, IFNα/β- and IFNλ-dependent immune responses were similar in the presence of either one of the STAT1 isoforms. Using site-directed chromatin immunoprecipitation (ChIP) analysis we are currently investigating the molecular mechanisms of the STAT1 isoform specificity in IFNγ-mediated transcriptional activation. Supported by the Austrian Science Fund (FWF, SFB-F28 , DK-W1212 ).