Abstract
CCR5 is a chemotactic mediator for inflammatory cells as well as regulatory T cells (Tregs). In this study, we investigated the role of CCR5 during infection with the fungal pathogen Histoplasma capsulatum. Mice lacking CCR5 or treated with an mAb to CCL4 had impaired infiltration of inflammatory cells to the lungs. Despite displaying an elevated fungal burden prior to activation of an adaptive immune response, CCL4-neutralized and CCR5(-/-) mice resolved infection more efficiently than controls. Accelerated fungal clearance was associated with a reduced number of Tregs in the lungs. Impaired trafficking was not solely responsible for the paucity of Tregs in the lungs, as proliferation of both CD4(+) T cells and Tregs was diminished in CCR5(-/-) lungs during infection. A reduced number of Tregs in CCR5(-/-) lungs was associated with a selective increase of Th17 cytokines, and neutralization of IL-17 increased Treg proliferation and consequently fungal burden in CCR5(-/-) mice. Thus, CCR5 dictates pathogen persistence by tightly regulating the balance between Treg and Th17 cells in H. capsulatum infection.