Differential Activation of the Transcription Factor IRF1 Underlies the Distinct Immune Responses Elicited by Type I and Type III Interferons

Author:

Forero, Adriana

Ozarkar, Snehal

Li,Hongchuan

Lee, Chia Heng

Hemann, Emily A

Nadjsombati, Marija S

Hendricks, Matthew R

So, Lomon

Green, Richard

Roy, Chandra N

Sarkar, Saumendra N

von Moltke, Jakob

Anderson,Steve

Gale, Michael

Savan, Ram
Author Address

Department of Immunology, School of Medicine, University of Washington, Seattle, WA 98109, USA., Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Department of Immunology, School of Medicine, University of Washington, Seattle, WA 98109, USA; Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109, USA., University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA., Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA; Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Department of Immunology, School of Medicine, University of Washington, Seattle, WA 98109, USA; Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA 98109, USA. Electronic address: savanram@uw.edu.,

Abstract:

Type I and III interferons (IFNs) activate similar downstream signaling cascades, but unlike type I IFNs, type III IFNs (IFN lambda) do not elicit strong inflammatory responses in vivo. Here, we examined the molecular mechanisms underlying this disparity. Type I and III IFNs displayed kinetic differences in expression of IFN-stimulated genes and proinflammatory responses, with type I IFNs preferentially stimulating expression of the transcription factor IRF1. Type III IFNs failed to induce IRF1 expression because of low IFN lambda receptor abundance and insufficient STAT1 activation on epithelial cells and thus did not activate the IRF1 proinflammatory gene program. Rather, IFN lambda stimulation preferentially induced factors implicated in tissue repair. Our findings suggest that IFN receptor compartmentalization and abundance confer a spatiotemporal division of labor where type III IFNs control viral spread at the site of the infection while restricting tissue damage; the transient induction of inflammatory responses by type I IFNs recruits immune effectors to promote protective immunity.

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