title: 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.
authors.affiliation: INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
authors.forename: Akil
authors.initials: A
authors.lastname: Hammami
authors.affiliation: INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
authors.forename: Tania
authors.initials: T
authors.lastname: Charpentier
authors.affiliation: INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
authors.forename: Mélina
authors.initials: M
authors.lastname: Smans
authors.affiliation: INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
authors.forename: Simona
authors.initials: S
authors.lastname: Stäger
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000276:immunology; D057131:Immune Evasion / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000276:immunology*; D007893:Leishmania donovani; D007898:Leishmaniasis, Visceral / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse