Editors' ChoiceImmunology

Hypoxia limits IgG-producing B cells

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Science Signaling  13 Sep 2016:
Vol. 9, Issue 445, pp. ec209
DOI: 10.1126/scisignal.aaj1881

As B cells pass through the different parts of lymph nodes, they experience different cytokine conditions and, as Cho et al. reported, different oxygen conditions. In the lymph node germinal center (GC), B cells proliferate, undergo class switching of their antibodies, and differentiate. GCs are not uniform but have distinct zones—called light zones and dark zones—and the B cells repeatedly encounter each type of zone as they develop and tune their antibodies. Cho et al. found that GC light zones were hypoxic and had increased abundance of the hypoxia-induced transcription factors (HIFs). Experiments with B cells cultured ex vivo under conditions that promote IgG class switching or IgA class switching revealed that hypoxia selectively reduced IgG class switching, which was associated with a reduction in the mRNA of the transcription factor T-bet and its target Iγ2c GLT, and in the mRNA and protein abundance of activation-induced cytosine deaminase (AID), an enzyme critical for the DNA rearrangements necessary for class switching. Hypoxia also reduced B cell proliferation (BrdU incorporation) and increased caspase activation, indicating an increase in apoptosis. Adoptive transfer of mature B cells with forced stabilization of HIF (pVHL-deficient) had similar IgA production as mice receiving wild-type cells but resulted in decreased production of IgG2c antibodies and fewer antigen-binding GC-derived B cells and fewer cells producing antigen-specific IgG2c, thus confirming that the HIF pathway was acting within the B cells to regulate class switching. B cells cultured under hypoxic conditions or in the presence of an inhibitor of PHD, an enzyme necessary for HIF destabilization, exhibited less activity of the pathway mediated by the kinase complex mTORC1 in response to stimulation of the B cell receptor. Selective reduction in mTORC1 by haploinsufficiency of the complex-encoding gene Raptor resulted in similar impairment of IgG class switching in culture and high-affinity IgG antibody production in vivo. These results may explain the reduced IgG in the circulation of patients with hypoxic lung disease and their increased susceptibility to infection.

S. H. Cho, A. L. Raybuck, K. Stengel, M. Wei, T. C. Beck, E. Volanakis, J. W. Thomas, S. Hiebert, V. H. Haase, M. R. Boothby, Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature 537, 234–238 (2016). [PubMed]

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