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

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 (O). However, it is essentially unknown if and how variations in O affect B cell differentiation, in particular for humans. Using optimized 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 O during culture - reminiscent of 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.