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J Immunol. 2016 Nov 15;197(10):4014-4020. Epub 2016 Oct 19.

Germinal Center Hypoxia Potentiates Immunoglobulin Class Switch Recombination.

Author information

1
New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115; robertkabbott@gmail.com.
2
New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA 02115.
3
Department of Immunology and Human Vaccine Institute, Duke University, Durham, NC 27710.
4
Department of Immunology, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan; and.
5
Laboratory of Immunobiology, Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115.

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% O2 during 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.

PMID:
27798169
PMCID:
PMC5123804
DOI:
10.4049/jimmunol.1601401
[Indexed for MEDLINE]
Free PMC Article

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