Abstract B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2 and T3 stages to become naïve B cells. We have identified a bifurcation of human B cell maturation from the T1 stage forming IgM hi and IgM lo developmental trajectories. IgM hi T2 cells have higher expression of α4β7 integrin and lower expression of IL4 receptor (IL4R) compared to the IgM lo branch and are selectively recruited into gut-associated lymphoid tissue. IgM hi T2 cells also share transcriptomic features with marginal zone B cells (MZB). Lineage progression from T1 cells to MZB via an IgM hi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgM hi gut homing T2 cells is observed in severe SLE and is associated with reduction of MZB and their putative IgM hi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence and importance for maintaining health.

Human marginal zone B cell development from early T2 progenitors