title: Germinal Center Hypoxia Potentiates Immunoglobulin Class Switch Recombination.
abstract: Germinal centers (GCs) are anatomic sites where B cells undergo secondary diversification to produce high-affinity, class-switched Abs. We hypothesized that proliferating B cells in GCs create a hypoxic microenvironment that governs their further differentiation. Using molecular markers, we found GCs to be predominantly hypoxic. Compared to normoxia (21% O2), hypoxic culture conditions (1% O2) in vitro accelerated class switching and plasma cell formation and enhanced expression of GL-7 on B and CD4+T cells. Reversal of GC hypoxia in vivo by breathing 60% O2during immunization resulted in reduced frequencies of GC B cells, T follicular helper cells, and plasmacytes, as well as lower expression of ICOS on T follicular helper cells. Importantly, this reversal of GC hypoxia decreased Ag-specific serum IgG1 and reduced the frequency of IgG1+B cells within the Ag-specific GC. Taken together, these observations reveal a critical role for hypoxia in GC B cell differentiation.
authors: New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115; robertkabbott@gmail.com.
authors: Robert K
authors: RK
authors: Abbott
authors: New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115.
authors: Molly
authors: 0000-0002-2957-9680
authors: M
authors: Thayer
authors: New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115.
authors: Jasmine
authors: 0000-0001-6078-5733
authors: J
authors: Labuda
authors: New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115.
authors: Murillo
authors: 0000-0003-4668-6290
authors: M
authors: Silva
authors: New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115.
authors: Phaethon
authors: 0000-0002-4927-8092
authors: P
authors: Philbrook
authors: Department of Immunology and Human Vaccine Institute, Duke University, Durham, NC 27710.
authors: Derek W
authors: DW
authors: Cain
authors: Department of Immunology, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan; and.
authors: Hidefumi
authors: H
authors: Kojima
authors: New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115.
authors: Stephen
authors: S
authors: Hatfield
authors: New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115.
authors: Shalini
authors: S
authors: Sethumadhavan
authors: New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115.
authors: Akio
authors: A
authors: Ohta
authors: Laboratory of Immunobiology, Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115.
authors: Ellis L
authors: 0000-0003-1048-5526
authors: EL
authors: Reinherz
authors: Department of Immunology and Human Vaccine Institute, Duke University, Durham, NC 27710.
authors: Garnett
authors: G
authors: Kelsoe
authors: New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115.
authors: Michail
authors: 0000-0002-9819-9729
authors: M
authors: Sitkovsky
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D002454:Cell Differentiation; D015687:Cell Hypoxia; D018858:Germinal Center / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007136:Immunoglobulins / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism; D010950:Plasma Cells / Q000276:immunology / Q000502:physiology; D011995:Recombination, Genetic
chemical_list: D007074:Immunoglobulin G; D007136:Immunoglobulins; D010100:Oxygen