Mice Deficient in T-bet Form Inducible NO Synthase-Positive Granulomas That Fail to Constrain Salmonella

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.