TY - JOUR
T1 - Mice deficient in T-bet form inducible NO synthase-positive granulomas that fail to constrain salmonella
AU - Perez-Toledo, Marisol
AU - Beristain-Covarrubias, Nonantzin
AU - Channel, William M.
AU - Hitchcoc, Jessica R.
AU - Cook, Charlotte N.
AU - Coughla, Ruth E.
AU - Bobat, Saeeda
AU - Jone, Nicholas D.
AU - Nakamura, Kyoko
AU - Ros, Ewan A.
AU - Rossite, Amanda E.
AU - Rooke, Jessica
AU - Garcia-Gimenez, Alicia
AU - Jossi, Sian
AU - Persaud, Ruby R.
AU - Marcial-Juarez, Edith
AU - Flores-Langarica, Adriana
AU - Henderso, Ian R.
AU - Wither, David R.
AU - Watson, Steve P.
AU - Cunningham, Adam F.
N1 - Publisher Copyright:
© 2020 American Association of Immunologists. All rights reserved.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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 STminfected 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.
AB - 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 STminfected 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.
UR - http://www.scopus.com/inward/record.url?scp=85088494185&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.2000089
DO - 10.4049/jimmunol.2000089
M3 - Article
C2 - 32591391
AN - SCOPUS:85088494185
SN - 0022-1767
VL - 205
SP - 708
EP - 719
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -