title: HIF-1α influences myeloid cell antigen presentation and response to subcutaneous OVA vaccination.
abstract: Hypoxia-inducible factor (HIF)-1 is a transcription factor known to play an important role in regulating the innate immune response to infection. Under baseline conditions, cellular HIF-1 levels in leukocytes are scarce, but levels rise rapidly in response to hypoxia or molecular signals of infection or inflammation such as microbial surface molecules and host-derived cytokines. Innate immune cells such as macrophages, neutrophils, and mast cells exhibit increased microbicidal activity when HIF-1 levels are increased, and mice lacking HIF-1 are more susceptible to invasive bacterial infection. In this study, we used genetic and pharmacologic means to determine whether HIF-1 also plays an important role in the adaptive immune response to infection. HIF-1α/Tie-2 Cre(+) mice harboring a >90 % knockdown of HIF-1 in myeloid cells were studied. We found antigen-presenting cells from these mice that expressed lower levels of MHC-II and the costimulatory molecules CD80 and CD86, and were less able to induce T cell proliferation. These differences were present at baseline and persisted after activation. Increasing HIF-1 levels in wild-type (WT) cells by using the prolyl hydroxylase inhibitor drug AKB-4924 had the opposite effect, increasing MHC and costimulatory molecule expression and T cell proliferation. In experimental vaccination, HIF-1α/Tie-2 Cre(+) mice exhibited a weaker T cell response and lower antibody levels in response to vaccination than WT mice, while WT mice treated with a drug to elevate HIF-1 responded more strongly to vaccination. Thus, HIF-1 participates in bridging the innate and adaptive immune responses and may merit further exploration as an adjuvant target.
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Bhandari
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate; D007279:Injections, Subcutaneous; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010879:Piperazines / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014611:Vaccination
chemical_list: C575838:AKB-4924; D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010879:Piperazines; D011728:Pyridones; D010047:Ovalbumin