Interferon‐γ‐ and glucocorticoid‐mediated pathways synergize to enhance death of CD4+ CD8+ thymocytes during Salmonella enterica serovar Typhimurium infection

SummaryThymic atrophy is known to occur during infections; however, there is limited understanding of its causes and of the cross‐talk between different pathways. This study investigates mechanisms involved in thymic atrophy during a model of oral infection by Salmonella enterica serovar Typhimurium (S. typhimurium). Significant death of CD4+ CD8+ thymocytes, but not of single‐positive thymocytes or peripheral lymphocytes, is observed at later stages during infection with live, but not heat‐killed, bacteria. The death of CD4+ CD8+ thymocytes is Fas‐independent as shown by infection studies with lpr mice. However, apoptosis occurs with lowering of mitochondrial potential and higher caspase‐3 activity. The amounts of cortisol, a glucocorticoid, and interferon‐γ (IFN‐γ), an inflammatory cytokine, increase upon infection. To investigate the functional roles of these molecules, studies were performed using Ifnγ−/− mice together with RU486, a glucocorticoid receptor antagonist. Treatment of C57BL/6 mice with RU486 does not affect colony‐forming units (CFU), amounts of IFN‐γ and mouse survival; however, there is partial rescue in thymocyte death. Upon infection, Ifnγ−/− mice display higher CFU and lower survival but more surviving thymocytes are recovered. However, there is no difference in cortisol amounts in C57BL/6 and Ifnγ−/− mice. Importantly, the number of CD4+ CD8+ thymocytes is significantly higher in Ifnγ−/− mice treated with RU486 along with lower caspase‐3 activity and mitochondrial damage. Hence, endogenous glucocorticoid and IFN‐γ‐mediated pathways are parallel but synergize in an additive manner to induce death of CD4+ CD8+ thymocytes during S. typhimurium infection. The implications of this study for host responses during infection are discussed.