title: Genetic deletion of the HIF-1α isoform I.1 in T cells enhances antibacterial immunity and improves survival in a murine peritonitis model.
abstract: Hypoxia-adenosinergic suppression and redirection of the immune response has been implicated in the regulation of antipathogen and antitumor immunity, with hypoxia-inducible factor 1α (HIF-1α) playing a major role. In this study, we investigated the role of isoform I.1, a quantitatively minor alternative isoform of HIF-1α, in antibacterial immunity and sepsis survival. By using the cecal ligation and puncture model of bacterial peritonitis, we studied the function of I.1 isoform in T cells using mice with total I.1 isoform deficiency and mice with T-cell-targeted I.1 knockdown. We found that genetic deletion of the I.1 isoform resulted in enhanced resistance to septic lethality, significantly reduced bacterial load in peripheral blood, increased M1 macrophage polarization, augmented levels of proinflammatory cytokines in serum, and significantly decreased levels of the anti-inflammatory cytokine IL-10. Our data suggest a previously unrecognized immunosuppressive role for the I.1 isoform in T cells during bacterial sepsis. We interpret these data as indicative that the activation-inducible isoform I.1 hinders the contribution of T cells to the antibacterial response by affecting M1/M2 macrophage polarization and microbicidal function.
authors.affiliation: New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Georgiev
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Belikoff
authors.forename: Stephen
authors.initials: S
authors.lastname: Hatfield
authors.forename: Akio
authors.initials: A
authors.lastname: Ohta
authors.forename: Michail V
authors.initials: MV
authors.lastname: Sitkovsky
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Lukashev
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D004195:Disease Models, Animal; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics*; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D010538:Peritonitis / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D020033:Protein Isoforms; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D018805:Sepsis / Q000235:genetics / Q000276:immunology / Q000401:mortality; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020033:Protein Isoforms; D011948:Receptors, Antigen, T-Cell