IL-12 as an immunopotentiator in leishmaniasis

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DESCRIPTION (provided by the applicant): Experimental Leishmania major infections in mice have been used extensively to understand how cell-mediated immunity (CMI) develops, and to specifically define the factors that dictate whether a Thl or Th2 response is observed after activation of T cells. Such studies have clearly shown an important role for IL-12 in the development of resistance and a Thl response. However, despite a great increase in our knowledge of the events that are associated with the development of Thl responses, little is understood about the rules that govern the maintenance of CMI. Our laboratory has recently shown that IL-12 is required not only to initiate Thl cell development, but also to maintain this response. This proposal seeks to determine how IL-12 participates in maintaining CMI, and in so doing will more broadly investigate how immunologic memory works in L. major healed mice. Our specific aims address the three critical components for CMI: memory T cell function (Aim 1), the antigen-in this case the role of parasite persistence (Aim 2), and the accessory cells-specifically dendritic cells-that both present antigen and influence the nature of the T cells that develop (Aim 3). The working hypothesis of this proposal is that CMI requires the constant renewal of the Thl population from a non-polarized pool of T cells. To test this hypothesis a series of adoptive transfer experiments are proposed, both with conventional T cells, as well as TCR transgenic T cells recognizing a leishmanial antigen. The donor cells will be followed in the recipient mice to assess their trafficking patterns, cytokine production and life span. An analysis of the role of parasite persistence will use a L. major (dhfr-ts-) thymidine auxotroph that infects mice, but fails to survive. Finally, the role of antigen presentation will be assessed by characterizing the dendritic cell response associated with resistance. Preliminary studies from this laboratory demonstrated that CD40-CD40L interactions are not required for maintenance of immunity, and in this aim, the compensatory role of TRANCE will be tested. Overall, these experiments should provide a clear picture of the dynamic interactions between T cells, dendritic cells and persisting parasites that are required to maintain cell-mediated immunity.