Humoral immunity and vaccine efficacy depend on the proliferation, affinity maturation and class switch recombination (CSR) of B cells in germinal centers (GCs). It is well appreciated that the cytokines present in this microenvironment determine the isotype to which differentiating B cells will switch. In this recent manuscript, Cho and colleagues find an important role for another factor, oxygen levels, in modulating the effector function of GC B cells. The proportion of oxygen (pO2) can vary from 21% in the atmosphere, to 5% in the venous blood, and 1% in the depth of certain tissues, such that cells may be exposed to various pO2 levels, depending on where they are in the body. The authors injected into mice chemical probes that mark hypoxic cells and showed that GC B cells were more hypoxic than other B cells in the spleen, and that the most hypoxic cells were found in the light zone of the GC, an area of less intense proliferation than the dark zone (Figure 1). Hypoxic B cells proliferated less and displayed increased apoptotic signaling both in vivo and in a hypoxic chamber in vitro. Hypoxia resulted in decreased switching to IgG1 and IgG2c isotypes (the latter an IFN-γ-driven isotype in C57BL/6 mice, analogous to IgG2a in other strains, and important for antimicrobial and inflammatory responses), even within B cells that had successfully proliferated several cycles. This was true in both primary and secondary immune responses. In contrast, hypoxia minimally affected IgA class switch, perhaps an adaptation to the fact that the intestine, where most IgA is produced, has low pO2 constitutively. Hypoxia also switched the metabolic program of activated B cells by promoting a higher glycolytic rate. Mechanistically, hypoxia reduced expression of activation-induced deaminase (AID, an enzyme that drives CSR) in IgG but not IgA switch conditions. Immunization of mice with conditional deletion of von Hippel–Lindau protein selectively in B cells, a trick to stabilize hypoxia-induced factor (HIF) and mimic hypoxia, recapitulated the HIF-dependent reduction of high affinity IgG1 antibodies and of IgG2c antibodies of all affinities. These defects, which were corrected if expression of AID was forced in B cells, correlated with reduced mammalian target of rapamycin complex 1 (mTORC1) activation. Diminished antibody production was mimicked by Rptr haploinsufficiency (a molecule necessary for mTORC1 activation). Of particular interest to transplant professionals, treatment of B cells with rapamycin also reduced AID levels and IgG2c switching. Therefore, the pO2 to which GC B cells are exposed determines their proliferation, survival, affinity maturation and CSR, and modulating local oxygen levels or influencing the signaling pathways elicited by hypoxia could potentially be a therapeutic strategy to manipulate humoral responses in disease. Alloantibody production in transplantation may be the main cause of chronic rejection and late graft loss, vexing attempts at increasing organs’ half-lives. Whereas primary humoral alloresponses are likely initiated in secondary lymphoid organs, tertiary lymphoid structures may develop over time within the transplanted organ itself. B cells from these structures may respond to cryptic self-antigens and undergo affinity maturation locally. The data from Cho and colleagues suggest that levels of pO2 in transplanted organs should be investigated. Thus, targeting rapamycin to GCs and to the graft, or manipulating oxygen levels locally, may be an approach to reduce initial production of alloantibodies and secondary epitope spreading to cryptic self-antigens. Dr. Alegre is a professor in the Department of Medicine at the University of Chicago.