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

Abstract

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 antigen-specific 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-1α in dendritic cells. Ablation of HIF-1α 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-1α in CD11c+ cells had a significantly lower splenic parasite burden, suggesting that induction of HIF-1α may represent an immune evasive mechanism adopted by Leishmania parasites to establish persistent infections.

Regulation of immunity and inflammation by hypoxia in immunological niches

“…By contrast, in macrophages, HIF regulates M1 and M2 polarization, motility, bactericidal activity and tumour development 48,49 . In dendritic cells (DCs), HIF modulates survival, migration, antigen presentation, interferon synthesis and differentiation 50,51 . Similarly, in T cells, HIF is important for the regulation of not only survival and differentiation but also proliferation and antitumour capacity 33 .…”

The role of myeloid-derived suppressor cells in chronic infectious diseases and the current methodology available for their study

“…The treatment of cells with siHIF‐1α decreases the parasitic burden, indicating that expression of HIF1‐α improves intracellular parasite growth . The use of a conditional HIF‐1α knockout mice in DCs supports this idea . These mice had lower parasite burden in spleen, better CD8 + T cell response, increased production of IL‐12, but lower production of IL‐6 and TNF‐α by splenic DCs .…”

Hypoxia inducible factor 1α: A critical factor for the immune response to pathogens and Leishmania

“…We have recently shown, using an experimental model for VL, that L. donovani promoted the stabilization of HIF-1α in DC by generating a highly proinflammatory microenvironment [133].…”

“…As expected, stabilization of HIF-1α had functional consequences on DCs as well. Indeed, analysis of T cell responses in mice with a targeted deletion of HIF-1α in CD11c + cells revealed that that HIF-1α upregulation impaired sustained IL-12 expression in splenic DCs and upregulated IL-10 expression [133]. This resulted in enhanced CD8 + T cell expansion, a higher frequency of effector CD8 + T cells, and significantly lower splenic parasite burden.…”

“…donovani infected, IRF-5-deficient mice, suggesting that the inflammatory response triggered during infection was responsible for HIF-1α stabilization and ultimately for the impairment of DC functions [133]. The contribution of HIF-1α on vascularization, especially during chronic infection, or on host cell's metabolism has not yet been investigated.…”