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 mi ce 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 ce lls within 48 h, In this report we examined the molecular mechanism un derlying this IL-12 unresponsiveness. Extinction of IL-12 signaling in BALB/c mice is due to a rapid down-regulation of IL-12R beta 2-chain mRNA expression in CD4(+) T cells. In contrast, IL-12R beta 2-chain mR NA expression was maintained on CD4+ T cells from resistant C57BL/6 mi ce. The down-regulation of the IL-12R beta 2-chain mRNA expression ih BALB/c CD4(+) T cells is a consequence of the early IL-4 production. I n this murine model of infection, a strict correlation is shown in viv o between expression of the IL-12R beta 2-chain in CD4(+) T cells and the development of a Th1 response and down-regulation of the mRNA beta 2-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 beta 2-chain mRNA expression and I L-12 responsiveness. The data presented here support the hypothesis th at the genetically determined susceptibility of BALB/c mice to infecti on with L. major Is primarily based on an up-regulation of IL-4 produc tion, which secondarily induces extinction of IL-12 signaling.