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‐γ (IFN‐γ) 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‐γ 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‐γ mRNA in CD4+ T cells. Similarly, lymph node cells from infected wild‐type 129 mice produced predominantly IFN‐γ 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.