Induction of IFNαβ enables Listeria monocytogenes to suppress macrophage activation by IFNγ

Type I and II interferons (IFNs alpha beta and.) have opposing effects on immune resistance to certain pathogenic bacteria. While IFN gamma generally plays a protective role, IFN alpha beta exacerbates Listeria monocytogenes and Mycobacterium tuberculosis infections. Our findings provided evidence that this increased susceptibility reflects a novel antagonistic cross talk between IFN alpha beta and IFN gamma. Macrophages infected with L. monocytogenes strains that induce IFN alpha beta production responded poorly to IFN gamma as measured by reduced phosphorylation of STAT1 and reduced IFN gamma-dependent gene expression. The impaired responsiveness to IFN gamma correlated with reduced expression of its receptor, IFNGR, by both infected and bystander macrophages. Downregulation of IFNGR was dependent on responsiveness to IFN alpha beta and mimicked by recombinant IFN beta. Mice lacking responsiveness to IFN alpha beta (IFNAR1(-/-)) retained high IFNGR expression, developed higher expression of MHC-II on macrophages and DCs, and were more resistant to systemic L. monocytogenes infection-but only in the presence of IFN gamma. Thus, the ability of IFN alpha beta to downregulate IFNGR provides an explanation for its ability to reduce responsiveness to IFN gamma and to increase host susceptibility to bacterial infection. It remains to be determined whether and how such antagonistic interferon crosstalk benefits the host.