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.
Highlights
Maintenance of a proper balance between inflammatory and anti-inflammatory responses is essential for achieving effective immunity against infectious pathogens while limiting collateral inflammatory damage to the tissue
Our data demonstrate that the inflammatory response induced by IRF-5 limits CD8+ T cell expansion and induces HIF-1α in dendritic cells
We investigate the role of IRF-5-mediated inflammation in regulating antigen-specific CD8+ T cell responses during L. donovani infection
Summary
Maintenance of a proper balance between inflammatory and anti-inflammatory responses is essential for achieving effective immunity against infectious pathogens while limiting collateral inflammatory damage to the tissue. Immunosuppressive responses are sometimes generated in excess This event often results in the strong inhibition of protective pro-inflammatory responses and leads to susceptibility to infectious pathogens, such as Plasmodium [1,2], Leishmania [3,4], lymphocytic choriomeningitis virus [5,6], and Mycobacteria spp. Experimental infection with L. donovani results in pathogen-induced disruption of the splenic microarchitecture, which involves both the disruption of the marginal zone and the B-cell follicles, and the progressive loss of stromal cells [14,15]. This disruption is mediated by TNF [16], a cytokine that is overexpressed during VL [17,18]. TNF deficient mice infected with L. donovani have a lower IL-10 mRNA accumulation in the spleen than do their wild type counterparts [14], suggesting that TNF may be involved as a positive regulator of IL-10 production
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