Oxygen level is a critical regulator of human B cell differentiation and IgG class switch recombination

Abstract

The generation of high-affinity antibodies requires an efficient germinal center (GC) response. As differentiating B cells cycle between GC dark and light zones they encounter different oxygen pressures (pO2). However, it is essentially unknown if and how variations in pO2 affect B cell differentiation, in particular for humans. Using optimized in vitro cultures together with in-depth assessment of B cell phenotype and signaling pathways, we show that oxygen is a critical regulator of human naive B cell differentiation and class switch recombination. Normoxia promotes differentiation into functional antibody secreting cells, while a population of CD27++ B cells was uniquely generated under hypoxia. Moreover, time-dependent transitions between hypoxic and normoxic pO2 during culture - reminiscent of in vivo GC cyclic re-entry - steer different human B cell differentiation trajectories and IgG class switch recombination. Taken together, we identified multiple mechanisms trough which oxygen pressure governs human B cell differentiation.

Optimal AID expression and efficient immunoglobulin class switch recombination are dependent on the hypoxia‐inducible factor

“…While it has been shown that hypoxia leads to contrasting effects on CSR [4, 6, 14], here we demonstrate that inactivation of the HIF transcription factor in murine CH12 B cells (independently of pleiotropic effects on metabolism, cell survival, or oxygen dependence) results in defective CSR and that this is due to the suboptimal induction of AID expression. This has implications for the effectiveness of the humoral response within the GCs, as regions of hypoxia and cytokine stimulation might potentiate AID expression to enforce the diversification of the BCR and to accomplish the establishment of highly specific and adaptive immunity.…”