Contribution of the STAT1alpha and STAT1beta isoforms to IFN-gamma mediated innate immunity

The transcription factor STAT1 is essential for interferon- (IFN) mediated protective immunity in humans and mice. Two splice isoforms of STAT1, STAT1α and STAT1β, differ with regard to a C-terminal transactivation domain, which is absent in STAT1β. Dimers of STAT1β are therefore considered transcriptionally inactive and potential competitive inhibitors of STAT1α. Contrasting this view, generation and analysis of mice deficient for either STAT1α or STAT1β demonstrated transcriptional activity of the STAT1β isoform and its enhancement of innate immunity. Gene expression profiling in primary cells revealed overlapping, but also non-redundant and gene-specific activities of STAT1α and STAT1β in response to IFNγ. Consistently, both isoforms mediated protective, IFNγ-dependent immunity against the bacterium Listeria monocytogenes, although with remarkably different efficiency. In contrast, STAT1α and STAT1β were largely redundant for transcriptional responses to IFNα/β and for IFNα/β-dependent antiviral activity. Collectively, our data shed new light on how STAT1 isoforms contribute to antimicrobial immunity. We treated macrophages of Stat1 delta alpha and Stat1 delta beta isoforms as well as Stat1 KO and Stat1 Wt mice with IFN gamma and Listeria to reveal differences in gene expression between isoforms and the two control genotypes.