Cell-intrinsic and cell-extrinsic metabolic programs have emerged as modulators of T cell biology. In Nature, Boothby and colleagues show in mice that germinal center (GC) light zones are hypoxic and that low oxygen tension alters B cell function by promoting a higher glycolytic rate, which increases B cell apoptosis, diminishes proliferation and impairs immunoglobulin class switching to the pro-inflammatory IgG2c isotype. Expression of the hypoxia-induced transcription factor HIF is higher in GC B cells than in other spleen B cells. Hypoxia or experimental stabilization of HIF in mice deficient in the tumor suppressor pVHL results in a reduction in high-affinity IgG1 and total IgG2c antibody responses, whereas IgA responses are not affected. This effect is due to lower expression of the cytidine deaminase AID in IgG2c-switching conditions but not in IgA-switching conditions. The induction of HIF inhibits the activity of the metabolic checkpoint complex mTORC1, and partial inhibition of mTORC1 has similar effects on antibody switching.

Nature 537, 234–238 (2016)