Mice deficient in T-bet form inducible NO synthase–positive granulomas that fail to constrain salmonella

Marisol Perez-Toledo, Noni Beristain Covarrubias, Will Channell, Jessica Hitchcock, Charlie Jones, Ruth Coughlan, Saeeda Bobat, Nick Jones, Kyoko Nakamura, Ewan Ross, Amanda Rossiter, Jessica Rooke, Alicia Garcia-Gimenez, Sian Jossi, Ruby Persaud, Edith Marcial-Juarez, Adriana Flores-Langarica, Ian Henderson, David Withers, Steve WatsonAdam Cunningham

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Abstract

Clearance of intracellular infections caused by Salmonella Typhimurium (STm) requires IFN-γ and the Th1-associated transcription factor T-bet. Nevertheless, whereas IFN-γ−/− mice succumb rapidly to STm infections, T-bet−/− mice do not. In this study, we assess the anatomy of immune responses and the relationship with bacterial localization in the spleens and livers of STm-infected IFN-γ−/− and T-bet−/− mice. In IFN-γ−/− mice, there is deficient granuloma formation and inducible NO synthase (iNOS) induction, increased dissemination of bacteria throughout the organs, and rapid death. The provision of a source of IFN-γ reverses this, coincident with subsequent granuloma formation and substantially extends survival when compared with mice deficient in all sources of IFN-γ. T-bet−/− mice induce significant levels of IFN-γ− after challenge. Moreover, T-bet−/− mice have augmented IL-17 and neutrophil numbers, and neutralizing IL-17 reduces the neutrophilia but does not affect numbers of bacteria detected. Surprisingly, T-bet−/− mice exhibit surprisingly wild-type–like immune cell organization postinfection, including extensive iNOS+ granuloma formation. In wild-type mice, most bacteria are within iNOS+ granulomas, but in T-bet−/− mice, most bacteria are outside these sites. Therefore, Th1 cells act to restrict bacteria within IFN-γ–dependent iNOS+ granulomas and prevent dissemination.
Original languageEnglish
Pages (from-to)708-719
Number of pages12
JournalJournal of Immunology
Volume205
Issue number3
Early online date17 Jul 2020
DOIs
Publication statusPublished - 1 Aug 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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