Setting in motion the immune mechanisms underlying genetically determined resistance and susceptibility to infection with Leishmania major

The murine model of infection with Leishmania major has allowed the demonstration of a causal relationship between, on the one hand, genetically determined resistance to infection and the development of a Thl CD4⁺ cell response, and on the other hand, genetically determined susceptibility and Th2 cell maturation. Using this murine model of infection, the role of cytokines in directing the functional differentiation pathway of CD4⁺ T cell precursors, has been demonstrated in vivo. Thus, IL-12 and IFN-γ have been shown to favour Thl cell development and IL-4 is crucial for the differentiation of Th2 responses. Maturation of a Th2 response in susceptible BALB/c mice following infection with L. major is triggered by the IL-4 produced during the first two days after parasite inoculation. This IL-4 rapidly renders parasite specific CD4⁺ T cells precursors unresponsive to IL-12. A restricted population of CD4⁺ T cells expressing the Vβ4Vα8 TCR heterodimer and recognizing a single epitope on the LACK (Leishmania Activated C-Kinase) antigen of L. major is responsible for this rapid production of IL-4, instructing subsequent differentiation towards the Th2 phenotype of CD4⁺ T cells specific for several parasite antigens.