IRF-5-Mediated Inflammation Limits CD8+ T Cell Expansion by Inducing HIF-1α and Impairing Dendritic Cell Functions during Leishmania Infection

Inflammation is known to be necessary for promoting, sustaining, and tuning CD8(+) T cell responses. Following experimental Leishmania donovani infection, the inflammatory response is mainly induced by the transcription factor IRF-5. IRF-5 is responsible for the activation of several genes encoding key pro-inflammatory cytokines, such as IL-6 and TNF. Here, we investigate the role of IRF-5-mediated inflammation in regulating antigenspecific CD8(+) T cell responses during L. donovani infection. Our data demonstrate that the inflammatory response induced by IRF-5 limits CD8(+) T cell expansion and induces HIF-1 alpha in dendritic cells. Ablation of HIF-1 alpha in CD11c(+) cells resulted into a higher frequency of short-lived effector cells (SLEC), enhanced CD8(+) T cell expansion, and increased IL-12 expression by splenic DCs. Moreover, mice with a targeted depletion of HIF-1 alpha in CD11c(+) cells had a significantly lower splenic parasite burden, suggesting that induction of HIF-1 alpha may represent an immune evasive mechanism adopted by Leishmania parasites to establish persistent infections.