RT Journal Article SR Electronic T1 The In Vivo Source of Type I and Type III IFNs is Pathogen Dependent JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.10.05.463160 DO 10.1101/2021.10.05.463160 A1 Marvin J. Sandoval A1 Hsiang-Chi Tseng A1 Heidi P. Risman A1 Sergey Smirnov A1 Qing Li A1 Jian-Da Lin A1 Amariliz Rivera A1 Russell K. Durbin A1 Sergei V. Kotenko A1 Joan E. Durbin YR 2021 UL http://biorxiv.org/content/early/2021/10/05/2021.10.05.463160.abstract AB Type I (-α, β) and type III (-λ) interferons (IFNs) are produced in response to virus infection and upregulate a largely overlapping set of IFN stimulated genes which mediate the protective effects of these antiviral cytokines. In vitro studies have demonstrated the redundancy of these two cytokine families which activate the same transcription factor, IFN stimulated gene factor 3 (ISGF3), via distinct ligands and receptors. However, in vivo, these IFN types do have distinct functions based on receptor distribution, but also ligand availability. Using a newly generated IFN-λ reporter mouse strain we have observed that both type I and type III IFNs are produced in response to respiratory tract infection by Newcastle disease virus (NDV) and influenza A virus (IAV). In the case of NDV these IFNs are synthesized by different cell types. Type I IFNs are produced primarily by alveolar macrophages, type III IFNs are made only by epithelial cells, and production of either is dependent on MAVS. While epithelial cells of the respiratory tract represent the primary target of IAV infection, we found that they did not significantly contribute to IFN-λ production, and IFN-λ protein levels were largely unaffected in the absence of MAVS. Instead we found that pDCs, a cell type known for robust IFN-α production via TLR/MyD88 signaling, were the major producers of IFN-λ during IAV infection, with pDC depletion during influenza infection resulting in significantly reduced levels of both IFN-α and IFN-λ. In addition, we were able to demonstrate that pDCs rely on type I IFN for optimal IFN-λ production. These studies therefore demonstrate that the in vivo producers of Type III IFNs in response to respiratory virus infection are pathogen dependent, a finding which may explain the varying levels of cytokine production induced by different viral pathogens.Competing Interest StatementThe authors have declared no competing interest.