Original Article

Journal of Molecular Medicine

, Volume 91, Issue 10, pp 1199-1205

First online:

HIF-1α influences myeloid cell antigen presentation and response to subcutaneous OVA vaccination

  • Tamara BhandariAffiliated withDepartment of Pediatrics, University of California San DiegoBiomedical Sciences Graduate Program, University of California San Diego
  • , Joshua OlsonAffiliated withDepartment of Pediatrics, University of California San Diego
  • , Randall S. JohnsonAffiliated withDepartment of Pediatrics, University of California San DiegoDepartment of Physiology, Development, and Neuroscience, University of Cambridge
  • , Victor NizetAffiliated withDepartment of Pediatrics, University of California San DiegoBiomedical Sciences Graduate Program, University of California San DiegoSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego Email author 

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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.

Keywords

Hypoxia-inducible factor Dendritic cell Antigen presentation Adjuvant Vaccination