Interferons (IFNs) establish a pecking order in a study by Rayamajhi and colleagues. When type I IFNs muffled type II during bacterial invasion, the bacteria won.

Although the protective type II cytokine, IFN-γ, was expressed after bacteria invaded, infected cells weren't listening. Listeria-infected macrophages up-regulated the type I IFNs, IFN-α and -β, which down-regulated IFN-γ receptors on the cell surface and thus stifled IFN-γ signals. Without IFN-α/β receptors, mice resisted Listeria. They expressed IFN-γ–dependent genes, indicating that IFN-γ had made contact with its receptors.

In demonstrating that IFN-α/β mutes IFN-γ, this team presents a new solution for a long-standing conundrum. Namely, why mice deficient in virus-fighting type I IFNs are protected from pathogenic bacteria like Listeria monocytogenes and Mycobacterium tuberculosis. Earlier studies postulated that IFN-α/β hinder bacterial clearance by triggering the immune-suppressing cytokine IL-10. If this were true, one might predict an increase in IFN-γ in the absence of IFN-α/β signals because IL-10 stifles IFN-γ. However, the authors found that with or without IFN-α/β receptors, mice produced IFN-γ after infection. The problem was instead that IFN-γ messages failed to send with IFN-α/β receptors intact.

Interferon cross talk may explain why IFN-β treatments work for many multiple sclerosis patients. Perhaps, speculate the authors, IFN-β intercepts inflammatory signals from IFN-γ by dampening expression of its receptors.