Human marginal zone B cell development from early T2 progenitors.

Thomas J Tull ,David D’cruz ,Pawan Dhami ,Jacqueline Hy Siu ,Susan John ,Cristina Lebrero‐Fernández ,Yuan Zhao ,David Fear ,Richard J Ellis ,Jeremy Sanderson ,William Guesdon ,Wayel Jassem ,Michael J Pitcher ,Mats Bemark ,Michelle Kleeman ,Ulrich D Kadolsky ,Michael G Robson ,Richard Groves ,Yogesh Kamra ,Susanne Heck ,Nedyalko Petrov ,Jo Spencer

doi:10.1084/jem.20202001

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.

Highlights

Transitional (TS) B cells are the immature B cells in human blood from which all mature B cells develop
Spanning tree progression of density normalized events (SPADE) on viSNE identified B cell subsets including TS B cells represented by CD27−IgD+CD24+++/++CD38+++/++ nodes that included CD10+ transitional stage 1 (T1) and T2 cells as well as CD10− T3 cells (Fig. 1 A; Qiu et al, 2011; Zhao et al, 2018)
To perform a deep phenotypic analysis of TS B cells, events within the TS B cell bubble identified in Fig. 1, A and B, were exported and reclustered by SPADE on viSNE using all expressed panel markers and grouped according to gradients of loss of CD10, CD38, and CD24 and gain of CD21 corresponding to T1, T2, and T3 stages of differentiation (Bemark, 2015; Fig. 1 B)

Summary

Introduction

Transitional (TS) B cells are the immature B cells in human blood from which all mature B cells develop. A B cell lineage split that is dependent on B cell receptor engagement and the serine/threonine kinase Taok is initiated at the T1 phase (Hammad et al, 2017). This directs B cells toward marginal zone B (MZB) cell fate, requiring subsequent Notch cleavage by a disintegrin and metalloproteinasecontaining protein 10 (ADAM10). A MZB precursor (MZP) population has been proposed that undergoes terminal differentiation to MZB following Notch 2 ligation and can be discriminated from naive B cells by expression of high levels of IgM (IgMhi), CD24, and the glycosylation-dependent epitope CD45RBMEM55 (referred to here as CD45RB). An additional CD45RBhi IgMhi population that lacks the ABCB1 cotransporter has previously been referred to as T39, the relationships among this subset, MZBs, and MZPs is unclear (Bemark et al, 2013; Descatoire et al, 2014; Koethe et al, 2011; Zhao et al, 2018)

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Results

Conclusion