The IL-4 rapidly produced in BALB/c mice after infection with Leishmania major down-regulates IL-12 receptor beta 2-chain expression on CD4+ T cells resulting in a state of unresponsiveness to IL-12.
Within 1 day of infection with Leishmania major, susceptible BALB/c mice produce a burst of IL-4 in their draining lymph nodes, resulting in a state of unresponsiveness to IL-12 in parasite-specific CD4+ T cells within 48 h. In this report we examined the molecular mechanism underlying this IL-12 unresponsiveness. Extinction of IL-12 signaling in BALB/c mice is due to a rapid down-regulation of IL-12R beta2-chain mRNA expression in CD4+ T cells. In contrast, IL-12R beta2-chain mRNA expression was maintained on CD4+ T cells from resistant C57BL/6 mice. The down-regulation of the IL-12R beta2-chain mRNA expression in BALB/c CD4+ T cells is a consequence of the early IL-4 production. In this murine model of infection, a strict correlation is shown in vivo between expression of the IL-12R beta2-chain in CD4+ T cells and the development of a Th1 response and down-regulation of the mRNA beta2-chain expression and the maturation of a Th2 response. Treatment of BALB/c mice with IFN-gamma, even when IL-4 has been produced for 48 h, resulted in maintenance of IL-12R beta2-chain mRNA expression and IL-12 responsiveness. The data presented here support the hypothesis that the genetically determined susceptibility of BALB/c mice to infection with L. major is primarily based on an up-regulation of IL-4 production, which secondarily induces extinction of IL-12 signaling.
Himmelrich
H
H
World Health Organization Immunology Research and Training Center, Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Parra-Lopez
C
C
Tacchini-Cottier
F
F
Louis
J A
JA
Launois
P
P
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000008:administration & dosage / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000502:physiology; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D053707:Receptors, Interleukin-12; D018418:Th2 Cells / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology
C508443:Il12rb2 protein, mouse; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma