AUTHOR=Koers Jana , Marsman Casper , Steuten Juulke , Tol Simon , Derksen Ninotska I. L. , ten Brinke Anja , van Ham S. Marieke , Rispens Theo 

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

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1082154

DOI=10.3389/fimmu.2022.1082154

ISSN=1664-3224

ABSTRACT=<p>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 (<italic>p</italic>O<sub>2</sub>). However, it is essentially unknown if and how variations in <italic>p</italic>O<sub>2</sub> affect B cell differentiation, in particular for humans. Using optimized <italic>in vitro</italic> 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<sup>++</sup> B cells was uniquely generated under hypoxia. Moreover, time-dependent transitions between hypoxic and normoxic <italic>p</italic>O<sub>2</sub> during culture - reminiscent of <italic>in vivo</italic> 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.</p>