Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system

Sung Hoon Cho, Ariel L. Raybuck, Kristy Stengel, Mei Wei, Thomas C. Beck, Emmanuel Volanakis, James W. Thomas, Scott Hiebert, Volker H. Haase, Mark R. Boothby

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

Abstract

Germinal centres (GCs) promote humoral immunity and vaccine efficacy. In GCs, antigen-activated B cells proliferate, express high-affinity antibodies, promote antibody class switching, and yield B cell memory. Whereas the cytokine milieu has long been known to regulate effector functions that include the choice of immunoglobulin class, both cell-autonomous and extrinsic metabolic programming have emerged as modulators of T-cell-mediated immunity. Here we show in mice that GC light zones are hypoxic, and that low oxygen tension (po2) alters B cell physiology and function. In addition to reduced proliferation and increased B cell death, low po2 impairs antibody class switching to the pro-inflammatory IgG2c antibody isotype by limiting the expression of activation-induced cytosine deaminase (AID). Hypoxia induces HIF transcription factors by restricting the activity of prolyl hydroxyl dioxygenase enzymes, which hydroxylate HIF-1α and HIF-2α to destabilize HIF by binding the von Hippel-Landau tumour suppressor protein (pVHL). B-cell-specific depletion of pVHL leads to constitutive HIF stabilization, decreases antigen-specific GC B cells and undermines the generation of high-affinity IgG, switching to IgG2c, early memory B cells, and recall antibody responses. HIF induction can reprogram metabolic and growth factor gene expression. Sustained hypoxia or HIF induction by pVHL deficiency inhibits mTOR complex 1 (mTORC1) activity in B lymphoblasts, and mTORC1-haploinsufficient B cells have reduced clonal expansion, AID expression, and capacities to yield IgG2c and high-affinity antibodies. Thus, the normal physiology of GCs involves regional variegation of hypoxia, and HIF-dependent oxygen sensing regulates vital functions of B cells. We propose that the restriction of oxygen in lymphoid organs, which can be altered in pathophysiological states, modulates humoral immunity.

Original languageEnglish (US)
Pages (from-to)234-238
Number of pages5
JournalNature
Volume537
Issue number7619
DOIs
StatePublished - Aug 8 2016
Externally publishedYes

ASJC Scopus subject areas

  • General

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