BALB/c mice bearing a transgenic IL-12 receptor beta 2 gene exhibit a nonhealing phenotype to Leishmania major infection despite intact IL-12 signaling.
In BALB/c mice infected with Leishmania major, early secretion of IL-4 leads to a Th2-type response and nonhealing. We explored the role of IL-4-induced down-regulation of the IL-12Rbeta2 chain in the establishment of this Th2 response. First, we showed that the draining lymph nodes of resistant C57BL/6 mice infected with L. major were enriched in CD4+/IL-12Rbeta2 chain+ cells producing IFN-gamma. Next, we demonstrated that BALB/c background mice bearing an IL-12Rbeta2-chain transgene manifested a nonhealing phenotype similar to wild-type littermates despite the persistence of their ability to undergo STAT4 activation. Finally, we found that such transgenic mice display more severe infection than wild-type littermates when treated with IL-12 7 days after infection, and under this condition, the mice display increased Leishmania Ag-induced IL-4 secretion. These studies indicate that although CD4+/IL-12Rbeta2 chain+ T cells are important components of the Th1 response, maintenance of IL-12Rbeta2 chain expression is not sufficient to change a Th2 response to a Th1 response in vivo and thus to allow BALB/c mice to heal L. major infection.
Nishikomori
R
R
Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Gurunathan
S
S
Nishikomori
K
K
Strober
W
W
D000818:Animals; D005819:Genetic Markers / Q000276:immunology; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D016130:Immunophenotyping; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000502:physiology* / Q000627:therapeutic use; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008198:Lymph Nodes / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C / Q000235:genetics* / Q000276:immunology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000276:immunology*; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics*; D053707:Receptors, Interleukin-12; D012720:Severity of Illness Index; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000276:immunology*
D005819:Genetic Markers; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D015847:Interleukin-4