HELPER T CELL SUBSETS IN LEISHMANIASIS

University Of California San Francisco, San Francisco CA

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Abstract

The murine model of Leishmania major infection has proven a robust experimental system for investigations of CD4+ subset differentiation in vivo with applications to many areas of immunobiology. The central tenet that has evolved from this model is that control of infection correlates with the presence of a strong Thl response that provides IFN-g required for activation of macrophages and restriction of parasite replication. Conversely, the susceptibility of strains on the BALB background has been correlated with development of an aberrant Th2 response that is not only unable to provide requisite macrophage-activating signals but also abrogates the generation and activities of Th1-type cytokines. The life cycle of this organism - replication within an MHC class II compartment of the mammalian macrophage - underlies this marked CD4+ response and establishes this model as an exceptional probe for understanding the critical decisions faced by helper T cells in mediating appropriate immune responses. Importantly, the switch decision must be made at the time of T cell priming, as illustrated by the timing restrictions necessary for interventions capable of redirecting the aberrant response of BALB/c mice to an immunoprotective Th1 response. By focusing on this early period, we have identified the immunodominant antigen recognized by mice in the early CD4+ response to this parasite and successfully immunized highly susceptible BALB/c mice using combinations of IL-12 with recombinant antigen. Further, we have identified critical requirements for IL-4 during priming in the aberrant BALB/c response, suggesting that the BALB/c susceptibility relates to inappropriate production and/or sensitivity to IL-4 during priming of naive T cells. This proposal seeks to dissect elements of the early interaction of the immune system with L. major in order to more fully understand the nature of the priming response for helper T cells. A series of three specific aims will examine (1) the nature of the immunodominant antigen by characterizing it capacity to protect BALB.B and BALB.K mice, identifying T cell epitopes that will facilitate targeting of altered ligands, and through creation of gene- targeted deletion mutants of the parasite; (2) the cell source for critical cytokines involved in the early development switch of Th1/Th2 cells that originate from the innate immune system; and (3) elucidation of co-stimulatory pathways for IL-4 production that we have identified to be aberrant in mice on the BALB background. Such studies should yield important information regarding the basis of CD4+ subset differentiation and mechanisms that underlie disease susceptibility, and will serve to focus future studies directed at identification of the gene that confers susceptibility of BALB mice to L. major such that human homologs might be found.