title: Genetically resistant mice lacking interleukin-12 are susceptible to infection with Leishmania major and mount a polarized Th2 cell response.
abstract: Mice with homologous disruption of the gene coding for either the p35 subunit or the p40 subunit of interleukin-12 (IL-12) and derived from a strain genetically resistant to infection with Leishmania major have been used to study further the role of this cytokine in resistance to infection and the differentiation of functional CD4+ T cell subsets in vivo. Wild-type 129/Sv/Ev mice are resistant to infection with L. major showing only small lesions which resolve spontaneously within a few weeks and develop a type 1 CD4+ T cell response. In contrast, mice lacking bioactive IL-12 (IL-12p35-/- and IL-12p40-/-) developed large, progressing lesions. Whereas resistant mice were able to mount a delayed-type hypersensitivity (DTH) response to Leishmania antigen, susceptible BALB/c mice as well as IL-12-deficient 129/Sv/Ev mice did not show any DTH reaction. To characterize the functional phenotype of CD4+ T cells triggered in infected wild-type mice and IL-12-deficient mice, the expression of mRNA for interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) in purified CD4+ lymph node cells was analyzed. Wild-type 129/Sv/Ev mice showed high levels of mRNA for IFN-gamma and low levels of mRNA for IL-4 which is indicative of a Th1 response. In contrast, IL-12- deficient mice and susceptible BALB/c mice developed a strong Th2 response with high levels of IL-4 mRNA and low levels of IFN-gamma mRNA in CD4+ T cells. Similarly, lymph node cells from infected wild-type 129 mice produced predominantly IFN-gamma in response to stimulation with Leishmania antigen in vitro whereas lymph node cells from IL-12-deficient mice and susceptible BALB/c mice produced preferentially IL-4. Taken together, these results confirm in vivo the importance of IL-12 in induction of Th1 responses and protective immunity against L. major.
authors.affiliation: Department of Infectious Diseases, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Mattner
authors.forename: J
authors.initials: J
authors.lastname: Magram
authors.forename: J
authors.initials: J
authors.lastname: Ferrante
authors.forename: P
authors.initials: P
authors.lastname: Launois
authors.forename: K
authors.initials: K
authors.lastname: Di Padova
authors.forename: R
authors.initials: R
authors.lastname: Behin
authors.forename: M K
authors.initials: MK
authors.lastname: Gately
authors.forename: J A
authors.initials: JA
authors.lastname: Louis
authors.forename: G
authors.initials: G
authors.lastname: Alber
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004198:Disease Susceptibility; D005260:Female; D007113:Immunity, Innate / Q000235:genetics; D018664:Interleukin-12 / Q000172:deficiency* / Q000235:genetics*; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000209:etiology* / Q000235:genetics* / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D018664:Interleukin-12