• atrophy;
  • cytokines;
  • glucocorticoids;
  • interferon- γ;
  • thymus


Thymic 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.