Human marginal zone B cell development from early T2 progenitors
Thomas J Tull, Michael J. Pitcher, William Guesdon, Jacqueline H. Y. Siu, Cristina Lebrero‐Fernández, Yuan Zhao, Nedyalko Petrov, Susanne Heck, Richard J. Ellis, Pawan Dhami, Ulrich D. Kadolsky, Michelle Kleeman, Yogesh Kamra, David J. Fear, Susan John, Wayel Jassem, Richard Groves, Jeremy Sanderson, Michael G. Robson, David D’Cruz, Mats Bemark, Jo Spencer
Abstract
B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2, and T3 stages to become naive B cells. We have identified a bifurcation of human B cell maturation from the T1 stage forming IgMhi and IgMlo developmental trajectories. IgMhi T2 cells have higher expression of α4β7 integrin and lower expression of IL-4 receptor (IL4R) compared with the IgMlo branch and are selectively recruited into gut-associated lymphoid tissue. IgMhi T2 cells also share transcriptomic features with marginal zone B cells (MZBs). Lineage progression from T1 cells to MZBs via an IgMhi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgMhi gut-homing T2 cells is observed in severe SLE and is associated with reduction of MZBs and their putative IgMhi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence in health.