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.
Highlights
T-bet in T cells is essential to clear Salmonella Typhimurium (STm)
An i.p. infection of WT mice with 105 attenuated strain STm SL3261 was used in all the studies described below and results in a systemic but nonlethal infection that starts resolving by day 21 postinfection
We found a lower frequency of CXCR3+ CD4+ T cells in both spleen and liver from T-bet2/2 compared with WT mice (Fig. 7F), we did not find a defect in the localization of CD3+ cells that surrounded inducible NO synthase (iNOS)+ granulomas that contain bacteria (Fig. 7G, 7H)
Summary
We have used mice deficient in IFN-g or T-bet to examine the anatomy of successful and unsuccessful immune responses in the spleen and liver by assessing where bacteria reside within infected tissues, with the immune response generated. These experiments showed that all of the mice controlled the infection at day 7, but that T-bet was essential only in T cells for clearance at later time points (Fig. 1E).
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