Salmonella typhimurium aroA- infection in gene-targeted immunodeficient mice: major role of CD4+ TCR-αβ cells and IFN-γ in bacterial clearance independent of intracellular location

Abstract

Due to the dependency on aromatic precursors, the growth of Salmonella typhimurium aroA- is limited in immunocompetent mice. Here we show that H-21-A β-/- mice (lacking MHC class II molecules and thus devoid of mature CD4+ TCR-αβ cells), TCR-β-/- mice (devoid of TCR-αβ cells), and IFN-γ R-/- mice (unresponsive to IFN-γ) are highly susceptible to S. typhimurium aroA- infection compared with heterozygous controls. In contrast, β 2m-deficient mice (lacking surface MHC class I and thus devoid of conventional CD8+ T cells) or TCR-δ-/- mice (devoid of TCR-γ δ cells) were equally as resistant to S. typhimurium aroA- infection as their heterozygous littermates. These findings emphasize the vital role of CD4+ TCR-αβ cells and IFN-γ in resistance against S. typhimurium aroA-. Sublethal inocula of S. typhimurium aroA- led to permanent infection in H-21-A β-/- mice, suggesting that bacterial starvation is insufficient for sterile clearance in immunocompetent mice and that MHC class II-dependent immune mechanisms are required for pathogen eradication. The TCR-β-/- mice suffered from salmonellosis more severely than the MHC class II-deficient mutants, suggesting an auxiliary function of CD8+ T cells. Recombinant S. typhimurium aroA-, secreting listeriolysin (Hly) of Listeria monocytogenes, are capable of escaping from the phagosome into the cytosol of the host cell. However, the course of infection of these recombinant S. typhimurium SL7207 Hlys and control strains did not differ in β 2m-/- mutants. This finding argues against direct correlation of cytosolic location of S. typhimurium SL7207 Hlys with CD8+ T cell dependency of protection.