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Gamma Interferon-Independent Effects of Interleukin-12 on Immunity to Salmonella enterica Serovar Typhimurium

Price, Jason D., Simpfendorfer, Kim R., Mantena, Radhakrishnam R., Holden, James, Heath, William R., van Rooijen, Nico, Strugnell, Richard A., Wijburg, Odilia L.C.
Infection and immunity 2007 v.75 no.12 pp. 5753-5762
Salmonella enterica subsp. enterica serovar Typhimurium, T-lymphocytes, disease control, flow cytometry, immunity, interferon-gamma, interleukin-12, interleukin-18, lymph nodes, macrophages, mice, microbial load, ovalbumin, pathogens, serotypes
Interleukin-12 (IL-12) and IL-18 are both central to the induction of gamma interferon (IFN-γ), and various roles for IL-12 and IL-18 in control of intracellular microbial infections have been demonstrated. We used IL-12p40⁻/⁻ and IL-18⁻/⁻ mice to further investigate the role of IL-12 and IL-18 in control of Salmonella enterica serovar Typhimurium. While C57BL/6 and IL-18⁻/⁻ mice were able to resolve attenuated S. enterica serovar Typhimurium infections, the IL-12p40⁻/⁻ mice succumbed to a high bacterial burden after 60 days. Using ovalbumin (OVA)-specific T-cell receptor transgenic T cells (OT-II cells), we demonstrated that following oral infection with recombinant S. enterica serovar Typhimurium expressing OVA, the OT-II cells proliferated in the mesenteric lymph nodes of C57BL/6 and IL-18⁻/⁻ mice but not in IL-12p40⁻/⁻ mice. In addition, we demonstrated by flow cytometry that equivalent or increased numbers of T cells produced IFN-γ in IL-12p40⁻/⁻ mice compared with the numbers of T cells that produced IFN-γ in C57BL/6 and IL-18⁻/⁻ mice. Finally, we demonstrated that removal of macrophages from S. enterica serovar Typhimurium-infected C57BL/6 and IL-12p40⁻/⁻ mice did not affect the bacterial load, suggesting that impaired control of S. enterica serovar Typhimurium infection in the absence of IL-12p40 is not due to reduced macrophage bactericidal activities, while IL-18⁻/⁻ mice did rely on the presence of macrophages for control of the infection. Our results suggest that IL-12p40, but not IL-18, is critical to resolution of infections with attenuated S. enterica serovar Typhimurium and that especially the effects of IL-12p40 on proliferative responses of CD4⁺ T cells, but not the ability of these cells to produce IFN-γ, are important in the resolution of infection by this intracellular bacterial pathogen.