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Infection and Immunity, December 2007, p. 5753-5762, Vol. 75, No. 12
0019-9567/07/$08.00+0     doi:10.1128/IAI.00971-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

CRC for Vaccine Technology,¹ Australian Bacterial Pathogenesis Program,² Department of Microbiology & Immunology, The University of Melbourne,³ The Walter and Eliza Hall Institute of Medical Research, Parkville VIC3010, Australia,⁴ Department of Molecular Cell Biology, Vrije Universiteit VUMC, Amsterdam, The Netherlands⁵

Received 17 July 2007/ Returned for modification 20 August 2007/ Accepted 2 September 2007

Interleukin-12 (IL-12) and IL-18 are both central to the induction of gamma interferon (IFN-), 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- in IL-12p40^–/– mice compared with the numbers of T cells that produced IFN- 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-, are important in the resolution of infection by this intracellular bacterial pathogen.

Published ahead of print on 17 September 2007.

Editor: A. J. Bäumler