Some of the early events underlying Th2 cell maturation and susceptibilityto Leishmania major infection in BALB/c mice

The first experimental evidence for the development of polarized CD4(+) Th1 and Th2 responses in vivo has been obtained using the murine model of infe ction with Leishmania major, an intracellular parasite of macrophages in th eir vertebrate host. Genetically determined resistance and susceptibility t o infection with this parasite have been clearly demonstrated to result fro m the development of polarized Th1 and Th2 responses, respectively. Using t his model system, the dominant role of cytokines in the induction of polari zed CD4(+) responses has been validated in vivo. The requisite role of IL-4 in mediating both Th2 differentiation and susceptibility to infection in B ALB/c mice has directed interest towards the search for evidence of IL-4 pr oduction early after infection and identification of its cellular source. W e have been able to demonstrate a burst of IL-4 production in susceptible B ALB/c mice within the first day of infection with L. major and could establ ish that this rapidly produced IL-4 instructed Th2 lineage commitment of su bsequently activated CD4(+) T cells and stabilized this commitment by downr egulating IL-12 R beta 2 chain expression, resulting in susceptibility to i nfection. Strikingly, this early IL-4 response to infection resulted from t he cognate recognition of a single epitope in a distinctive antigen, LACK, from this complex microorganism by a restricted population of CD4(+) T cell s that express V beta 4-V alpha 8 T cell receptors.