title: Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system.
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 () 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.
authors: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors: Sung Hoon
authors: SH
authors: Cho
authors: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors: Ariel L
authors: AL
authors: Raybuck
authors: Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors: Kristy
authors: K
authors: Stengel
authors: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors: Mei
authors: M
authors: Wei
authors: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors: Thomas C
authors: TC
authors: Beck
authors: Department of Pediatrics, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors: Emmanuel
authors: E
authors: Volanakis
authors: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA.|Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors: James W
authors: JW
authors: Thomas
authors: Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232, USA.|Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors: Scott
authors: S
authors: Hiebert
authors: Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232, USA.|Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232, USA.|Medical and Research Services, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee 37212, USA.
authors: Volker H
authors: VH
authors: Haase
authors: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA.|Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232, USA.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee 37232, USA.|Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors: Mark R
authors: MR
authors: Boothby
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002470:Cell Survival; D043525:Cytosine Deaminase / Q000378:metabolism; D018858:Germinal Center / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D000860:Hypoxia / Q000276:immunology* / Q000378:metabolism*; D017578:Immunoglobulin Class Switching; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000906:Antibodies; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D043525:Cytosine Deaminase