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.

Dendritic Cell (DC)-Based Protection Against an Intracellular Pathogen Is Dependent Upon DC-Derived IL-12 and Can Be Induced by Molecularly Defined Antigens

“…Several studies have identified IL-12 as a key component in the development of the early immune response after Leishmania infection (29,44). DC have been shown to mediate the priming of Leishmania-specific T cells (49) and to produce high levels of IL-12 after exposure to parasite Ag (18,19), thus promoting the development of protective Th1 cells.…”

“…The mice were purchased from Charles River Breeding Laboratories (Sulzfeld, Germany) and, during experimentation, were kept under conventional conditions in an isolation facility. IL-12p35 Ϫ/Ϫ mice were generated as described (29) and backcrossed into a BALB/c background (30).…”

Effective clearance of intracellular Leishmania majorin vivo requires Pten in macrophages

“…A reduction in IL-12 production or an increase in IL-10 secretion results in an imbalance of Th1/Th2 cytokines that impairs healing during the later stages of Leishmania infection [46,47]. To characterize the T cell response associated with L. major infection in LysMCrePten flox/flox mice, we determined the cytokine profile produced by cells in the draining LN of Pten flox/flox and LysMCrePten flox/flox mice 4 wk after infection with L. major.…”

Genetic control of susceptibility to infection with Mycobacterium tuberculosis in mice

“…50,51 Introduction of a null allele at the IL-12 locus on a C57Bl/6J genetic background abrogates natural resistance to infection with M. tuberculosis, 52 and Leishmania major. 53 Finally, IL-6 and its receptor (IL-6R, one subunit of which maps on Chr.3) act synergistically with a number of other growth factors and cytokines to sustain normal proliferation and maturation of macrophages, T and B cells, and megakaryocytes. 49 IL-6 also behaves as an anti-inflammatory cytokine to control local and systemic inflammatory responses.…”