Interleukin-12 is essential for a protective Th1 response in mice infected with Cryptococcus neoformans.
To analyze the roles of interleukin-12 (IL-12) and the IL-12-dependent Th1 response in resistance to Cryptococcus neoformans, we have established a chronic infection model in wild-type mice and in mice with targeted disruptions of the genes for the IL-12p35 and IL-12p40 subunits (IL-12p35(-/-) and IL-12p40(-/-) mice, respectively) as well as in mice with a targeted disruption of the IL-4 gene. Long-term application of exogenous IL-12 prevented death of infected wild-type mice for the entire period of the experiment (up to 180 days) but did not resolve the infection. Infected IL-12p35(-/-) and IL-12p40(-/-) mice died significantly earlier than infected wild-type mice, whereas infection of IL-4-deficient mice led to prolonged survival. Interestingly, infected IL-12p40(-/-) mice died earlier and developed higher organ burdens than IL-12p35(-/-) mice, which, for the first time in an infection model, suggests a protective role of the IL-12p40 subunit independent of the IL-12 heterodimer. The fungal organ burdens of IL-4-deficient mice and IL-12-treated wild-type mice were significantly reduced compared to those of untreated wild-type mice and IL-12-deficient mice. Histopathological analysis revealed reduction of the number of granulomatous lesions following treatment with IL-12. Susceptibility of both IL-12p35(-/-) and IL-12p40(-/-) mice was associated with marginal production of gamma interferon and elevated levels of IL-4 from CD4(+) T cells, which indicates Th2 polarization in the absence of IL-12, whereas wild-type mice developed a Th1 response. Taken together, our data emphasize the essential role of IL-12 for protective Th1 responses against C. neoformans.
Decken
K
K
Department of Infectious Diseases, F. Hoffmann-La Roche AG, Basel, Switzerland.
Köhler
G
G
Palmer-Lehmann
K
K
Wunderlin
A
A
Mattner
F
F
Magram
J
J
Gately
M K
MK
Alber
G
G
D000818:Animals; D001921:Brain / Q000382:microbiology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D003453:Cryptococcosis / Q000276:immunology* / Q000401:mortality; D004195:Disease Models, Animal; D006099:Granuloma; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000172:deficiency / Q000276:immunology*; D015847:Interleukin-4 / Q000172:deficiency / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D013154:Spleen / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma