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

• Published in: Nature (London) Vol. 537; no. 7619; pp. 234 - 238
• Main Authors: Cho, Sung Hoon, Raybuck, Ariel L, Stengel, Kristy, Wei, Mei, Beck, Thomas C, Volanakis, Emmanuel, Thomas, James W, Hiebert, Scott, Haase, Volker H, Boothby, Mark R
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 08.09.2016
• Subjects: 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; Hypoxia; Hypoxia - immunology; Hypoxia - metabolism; Immunoglobulin Class Switching; Immunoglobulins; Inflammation; Lymph nodes; Lymphatic system; Mechanistic Target of Rapamycin Complex 1; Medical research; Metabolism; Mice; Mice, Inbred C57BL; Multiprotein Complexes - metabolism; Physiological research; Proteins; TOR Serine-Threonine Kinases - metabolism; Transcription factors; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature19334

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 () 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). 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.