Human marginal zone B cell development from early T2 progenitors

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 IgM(hi) and IgM(lo) developmental trajectories. IgM(hi) T2 cells have higher expression of α4β7 integrin and lower expression of IL-4 receptor (IL4R) compared with 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 (MZBs). Lineage progression from T1 cells to MZBs 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 MZBs and their putative IgM(hi) precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence in health.