IL-12Rbeta2-deficient mice of a genetically resistant background are susceptible to Leishmania major infection and develop a parasite-specific Th2 immune response.
The cytokine IL-12 plays a critical role in inducing the production of IFN-gamma from T and NK cells and in the polarization of T cells towards the Th1 phenotype. IL-12 is comprised of two subunits (IL-12p40 and IL-12p35) that together form the biologically active p70 molecule, and IL-12 functions via binding to a heterodimeric receptor (IL-12Rbeta1 and IL-12Rbeta2). Previous studies utilizing mice deficient for either the IL-12 cytokine or the IL-12-induced signaling molecule STAT4 have established a critical role for IL-12 during infection with Leishmania major. However, these studies warrant careful re-interpretation in light of the recent discovery of the IL-12-related cytokine, IL-23, which utilizes the IL-12p40 chain in combination with an IL-12p35-related molecule, called p19, and a receptor comprised of the IL-12Rbeta1 chain plus a unique chain referred to as IL-23R. We analyzed the course of L. major infection in mice deficient for the IL-12-specific IL-12Rbeta2 subunit in order to assess the role of IL-12 signaling without disruption of the IL-23 pathway. After infection with L. major, IL-12Rbeta2KO mice of a resistant background (C57Bl/6) developed large cutaneous lesions similar to those developed by susceptible BALB/c mice. Draining lymph node cells from L. major-infected IL-12Rbeta2KO mice released the Th2 cytokines IL-4 and IL-5 after in vitro stimulation with Leishmania lysate but were completely devoid of IFN-gamma, consistent with a default towards a strong parasite-specific Th2 response. L. major-infected IL-12Rbeta2KO mice were also devoid of parasite-specific IgG2a antibodies, and interestingly, their footpad lesions ulcerated earlier than those of susceptible BALB/c mice.
Chakir
Habiba
H
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ont., Canada K1H 8M5.
Campos-Neto
Antonio
A
Mojibian
Majid
M
Webb
John R
JR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000953:Antigens, Protozoan / Q000276:immunology; D004198:Disease Susceptibility / Q000276:immunology; D005786:Gene Expression Regulation; D007074:Immunoglobulin G / Q000096:biosynthesis; D007136:Immunoglobulins / Q000032:analysis / Q000097:blood; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology*; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology / Q000254:growth & development; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000953:Antigens, Protozoan; D007074:Immunoglobulin G; D007136:Immunoglobulins; D018664:Interleukin-12