Gamma interferon-independent effects of interleukin-12 on immunity to Salmonella enterica serovar Typhimurium.
Interleukin-12 (IL-12) and IL-18 are both central to the induction of gamma interferon (IFN-gamma), 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-gamma in IL-12p40(-/-) mice compared with the numbers of T cells that produced IFN-gamma 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-gamma, are important in the resolution of infection by this intracellular bacterial pathogen.
Price
Jason D
JD
CRC for Vaccine Technology and Department of Microbiology & Immunology, The University of Melbourne, Parkville VIC3010, Australia.
Simpfendorfer
Kim R
KR
Mantena
Radhakrishnam R
RR
Holden
James
J
Heath
William R
WR
van Rooijen
Nico
N
Strugnell
Richard A
RA
Wijburg
Odilia L C
OL
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000172:deficiency / Q000276:immunology*; D020382:Interleukin-18 / Q000172:deficiency / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000276:immunology; D012485:Salmonella typhi / Q000276:immunology*; D014435:Typhoid Fever / Q000276:immunology*; D000096743:Interferon gamma Receptor
D000942:Antigens, Bacterial; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007371:Interferon-gamma; D053762:Interleukin-12 Subunit p40; D020382:Interleukin-18; D010047:Ovalbumin; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor