Journal
JOURNAL OF IMMUNOLOGY
Volume 197, Issue 10, Pages 4014-4020Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1601401
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Funding
- National Institutes of Health [U19 AI 091693]
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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% O-2), hypoxic culture conditions (1% O-2) 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% O-2 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.
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