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 inpO2affect B cell differentiation, in particular for humans. Using optimizedin vitrocultures 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 normoxicpO2during culture - reminiscent ofin vivoGC 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.