Leishmania-encoded orthologs of macrophage migration inhibitory factor regulate host immunity to promote parasite persistence

Leishmania major encodes 2 orthologs of the cytokine macrophage migration inhibitory factor (MIF), whose functions in parasite growth or in the host-parasite interaction are unknown. To determine the importance of Leishmania-encoded MIF, both LmMIF genes were removed to produce an mif^-/- strain of L. major. This mutant strain replicated normally in vitro but had a 2-fold increased susceptibility to clearance by macrophages. Mice infected with mif^-/- L. major, when compared to the wild-type strain, also showed a 3-fold reduction in parasite burden. Microarray and functional analyses revealed a reduced ability of mif^-/- L. major to activate antigen-presenting cells, resulting in a 2-fold reduction in T-cell priming. In addition, there was a reduction in inflammation and effector CD4 T-cell formation in mif^-/- L. major-infected mice when compared to mice infected with wild-type L. major. Notably, effector CD4 T cells that developed during infection with mif^-/- L. major demonstrated statistically significant differences in markers of functional exhaustion, including increased expression of IFN-γ and IL-7R, reduced expression of programmed death-1, and decreased apoptosis. These data support a role for LmMIF in promoting parasite persistence by manipulating the host response to increase the exhaustion and depletion of protective CD4 T cells.