IL-12 is required for natural killer cell activation and subsequent T helper 1 cell development in experimental leishmaniasis.
Infection of mice with the protozoan Leishmania major is an established in vivo model for the definition of factors that contribute to CD4+ T helper cell subset development. In the current study, a central role for IL-12 in directing both the innate and adaptive immune responses to L. major is established. We show that in vivo neutralization of IL-12 eliminates the NK cell cytotoxic response and IFN-gamma production by lymph node cells from 2-day L. major-infected C3H mice. Moreover, anti-IL-12 treatment abrogated Th1 cell development and enhanced Th2 cell development. Consistent with these results, elevated IL-12 p40 production and an increase in the number of IL-12 p40-producing cells were observed within 1 day of infection in C3H mice. Because BALB/c mice lack an early NK cell response or a Th1-type immune response after L. major infection, we investigated the possibility that they had a defect in the ability to produce IL-12. Surprisingly, L. major infection stimulated IL-12 p40 production in BALB/c mice early after infection. Further studies suggest that BALB/c mice are unable to generate an early IFN-gamma response because of the simultaneous production of IL-12 and cytokines that inhibit IL-12 function, such as TGF-beta, IL-4, and IL-10. Together, these data show that IL-12 regulates the immune response to L. major, but that even when IL-12 is induced, Th1 cell development may be interrupted by simultaneous production of inhibitory cytokines.
Scharton-Kersten
T
T
Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia 19104, USA.
Afonso
L C
LC
Wysocka
M
M
Trinchieri
G
G
Scott
P
P
D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology*; D018320:Leishmania major / Q000276:immunology; D007896:Leishmaniasis / Q000276:immunology* / Q000473:pathology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology; D018417:Th1 Cells / Q000276:immunology*
D000953:Antigens, Protozoan; D016207:Cytokines; D018664:Interleukin-12; D007371:Interferon-gamma