HIF-1α influences myeloid cell antigen presentation and response to subcutaneous OVA vaccination
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.
KeywordsHypoxia-inducible factor Dendritic cell Antigen presentation Adjuvant Vaccination
We would like to thank Stephen Hedrick for providing us with the OT-I and OT-II mice, Robert Shalwitz and Anna Kotsakis of Aerpio Therapeutics for providing AKB-4924, and Davorka Messmer and Rebecca Saenz for their invaluable advice on experimental design. Research was provided by NIH/NIAID grants 093451 and 090863 to VN. TB was supported through the UCSD NIH/NIGMS Training Program in Molecular and Cellular Pharmacology (T32 007752) and the UCSD NIH/NIAMS Dermatology Investigator Training Program (T32 062496).
Conflict of interest
Randall Johnson, who provided the KO mice, is on SAB of Aerpio Therapeutics, who provided AKB-4924 HIF agonist. Victor Nizet and Aerpio Therapeutics have collaborated on NIH and Department of Defense grants. Aerpio Therapeutics had no interest in the design or reporting of the present study.
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