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

Deobagkar-Lele, M; Chacko, SK; Victor, ES; Kadthur, JC; Nandi, D

Journal article

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

Abstract:: 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.

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Deobagkar-Lele, M., Chacko, S. K., Victor, E. S., Kadthur, J. C., & Nandi, D. (2013). Interferon-γ- and glucocorticoid-mediated pathways synergize to enhance death of CD4(+) CD8(+) thymocytes during Salmonella enterica serovar Typhimurium infection. Immunology, 138(4), 307–321.

MLA Style

Deobagkar-Lele, M., et al. “Interferon-γ- and Glucocorticoid-Mediated Pathways Synergize to Enhance Death of CD4(+) CD8(+) Thymocytes during Salmonella Enterica Serovar Typhimurium Infection.” Immunology, vol. 138, no. 4, Wiley, 2013, pp. 307–21.

Chicago Style

Deobagkar-Lele, M, SK Chacko, ES Victor, JC Kadthur, and D Nandi. 2013. “Interferon-γ- and Glucocorticoid-Mediated Pathways Synergize to Enhance Death of CD4(+) CD8(+) Thymocytes during Salmonella Enterica Serovar Typhimurium Infection.” Immunology 138 (4): 307–21.
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