Germinal center hypoxia potentiates immunoglobulin class switch recombination

Robert K. Abbott, Molly Thayer, Jasmine Labuda, Murillo Silva, Phaethon Philbrook, Derek W. Cain, Hidefumi Kojima, Stephen Hatfield, Shalini Sethumadhavan, Akio Ohta, Ellis L. Reinherz, Garnett Kelsoe, Michail Sitkovsky

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4014-4020
Number of pages7
JournalJournal of Immunology
Volume197
Issue number10
DOIs
StatePublished - Nov 15 2016
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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