Role of Regulatory T cells in Leishmania major infection

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DESCRIPTION (provided by the applicant): Latent infections are an essential part of the human condition. The achievement of latency provides clear benefits to the host. In addition to halting microbe-mediated damage, we have shown that latent infection can be essential for the maintenance of immunity to reinfection. On the other hand, latency allows for the possibility of disease reactivation, and facilitates microbial dispersal to new hosts. Latency can thus benefit both host and pathogen. Using murine models, we have shown that CD4+CD25+ regulatory T cells (Treg) are essential for the development and maintenance of latent cutaneous infection Leishmania major. Treg rapidly accumulate at sites of infection with Lm, suppressing the ability of the immune response to completely eliminate the parasite. This achievement of latency is tightly linked to the dynamics of Treg accumulation at the site of infection. The inter-related hypotheses underlying these studies are that: (a) host/parasite interactions in infected icroenvironments drive the specific migration of Treg to such sites; (b) the dynamics of Treg accumulation at sites of infection are prime determinants of the efficiency of pathogen clearance and the development of concomitant immunity; (c) Treg regulate local immune responses by modulating the function of both APC and effector T cells; and (d) Treg modulate APC function largely though the release of IL-10. The goal of the current proposal is to define the mechanisms by which Treg modulate the immune response to leishmanial infection. We aim to: (1) Define the mechanisms underlying the specific recruitment of Treg to sites of infection with L. major; and (2) Determine the mechanisms underlying Treg-mediated modulation of immune responses to L. major both in vitro and in vivo.