Influence of the enzyme indoleamine-2,3-dioxygenase (IDO) in the differentiation and function of dendritic cells and regulatory T cells in the pulmonary paracoccidioidomycosis of resistant and susceptible mice to P. brasiliensis infection

Abstract

Paracoccidioides brasiliensis is a pathogenic fungus restricted to Latin America and its natural route of infection is the inhalation of fungal particles. In paracoccidioidomycosis (PCM), the regulatory mechanisms mediated by innate and cellular immunity are still unclear. Indoleamine 2,3-dioxygenase (IDO) is an IFN-gamma induced enzyme which catalyzes the tryptophan metabolism along the kynurenine pathway. It is known that IDO can control host-pathogen interaction by inhibiting the proliferation of intracellular microorganisms due to tryptophan starvation and by its immunosuppressive effect on T cell immunity. We have previously investigated the role of IDO in pulmonary PCM of susceptible (B10.A) and resistant (AJ) mice using control and 1-methyl-DL-tryptophan (1MT, an IDO inhibitor)-treated mice. Early in infection of susceptible mice, IDO was shown to reduce fungal loads and to decrease the number and activation of inflammatory CD4+ and CD8+ T cells that migrate to the lungs. In resistant mice, IDO controls early fungal loads, but exerts a suppressive effect on T cell immunity only at week 8 post infection. In both mouse strains IDO was shown to exert a dual role by diminishing fungal burdens but also suppressing T cell immunity due to its stimulatory effect on the expansion of regulatory T cells. This project was aimed to better study the influence of IDO on the behavior of dendritic and regulatory T cells in the course of the infection of susceptible and resistant mice. This work will clarify some important aspects on the immunosuppression associated with the severe forms of PCM and will possibly open new perspectives to the immunotherapy of this important systemic mycosis. (AU)