Identifying the initiating events of anti-Listeria responses using mice with conditional loss of IFN-γ receptor subunit 1 (IFNGR1)

Sang Hun Lee, Javier A. Carrero, Ravindra Uppaluri, J. Michael White, Jessica M. Archambault, Koon Siew Lai, Szeman Ruby Chan, Kathleen C.F. Sheehan, Emil R. Unanue, Robert D. Schreiber

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Although IFN-γis required for resolution of Listeria monocytogenesinfection, the identities of the IFN-γ-responsive cells that initiate the process remain unclear. We addressed this question using novel mice with conditional loss of IFN-γR (IFNGR1). Itgax-cre+ Ifngr1f/f mice with selective IFN-γunresponsiveness in CD8a+ dendritic cells displayed increased susceptibility to infection. This phenotype was due to the inability of IFN-γ-unresponsive CD8a+ dendritic cells to produce the initial burst of IL-12 induced by IFN-γfrom TNF-α-Activated NK/NKT cells. The defect in early IL-12 production resulted in increased IL-4 production that established a myeloid cell environment favoringListeriagrowth. Neutralization of IL-4 restoredListeriaresistance inItgax-cre+ Ifngr1f/f mice. We also found thatItgax-cre+ Ifngr1f/f mice survived infection with low-doseListeriaas the result of a second wave of IL-12 produced by Ly6Chi monocytes. Thus, an IFN-γ-driven cascade involving CD8a+ dendritic cells and NK/NKT cells induces the rapid production of IL-12 that initiates the anti-Listeria response.

Original languageEnglish
Pages (from-to)4223-4234
Number of pages12
JournalJournal of Immunology
Volume191
Issue number8
DOIs
StatePublished - Oct 15 2013

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