Journal Article

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

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

2016

Overview

Hypoxia in germinal centres regulates B cell class switching via its effects on mTOR complex 1 and activation-induced cytosine deaminase activity. Oxygen restriction in germinal centres Oxygen delivery and local hypoxia have been extensively studied in solid tumours in relation to immunobiology of cancer, but little is known about the microanatomy of oxygen concentrations around cells in different zones of the secondary lymphoid organs. This paper shows that oxygen — the supply of which is central to intermediary metabolism — is naturally restricted in germinal centres and influences B-lymphocyte function. Specifically, Mark Boothby and colleagues show that germinal centre hypoxia regulates antibody class switching via its effects on the activity of mTOR complex 1 and the cytosine deaminase AID. 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 1 , 2 . Whereas the cytokine milieu has long been known to regulate effector functions that include the choice of immunoglobulin class 3 , 4 , both cell-autonomous 5 and extrinsic 6 , 7 metabolic programming have emerged as modulators of T-cell-mediated immunity 8 . Here we show in mice that GC light zones are hypoxic, and that low oxygen tension ( ) alters B cell physiology and function. In addition to reduced proliferation and increased B cell death, low 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) 7 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/31 / 13/95 / 14/19 / 14/34 / 631/250/1619/40/2508 / 631/250/2152/2153/1982 / 631/250/2152/2498 / 631/250/2503 / 64/60 / 96/1 / 96/95 / Animals / Anoxia / Antibodies / Antibodies - immunology / Antigens / B cells / B-Lymphocytes - cytology / B-Lymphocytes - immunology / B-Lymphocytes - metabolism / Cell Hypoxia / Cell Proliferation / Cell Survival / Cytokines / Cytosine Deaminase - metabolism / Gene expression / Germinal Center - cytology / Germinal Center - immunology / Germinal Center - metabolism / Humanities and Social Sciences / Hypoxia / Hypoxia - immunology / Hypoxia - metabolism / Immunoglobulin Class Switching / Immunoglobulins / Inflammation / letter / Lymph nodes / Lymphatic system / Mechanistic Target of Rapamycin Complex 1 / Medical research / Metabolism / Mice / Mice, Inbred C57BL / multidisciplinary / Multiprotein Complexes - metabolism / Oxygen / Physiological research / Physiology / Proteins / Science / TOR Serine-Threonine Kinases - metabolism / Transcription factors