Control of B-1a cell development by instructive BCR signaling

Abstract

B-1a cells remain one of the most enigmatic lymphocyte subsets. In this review, we discuss recent advances in our understanding of the development of these cells and their regulation by the transcription factors Bhlhe41 and Arid3a as well as by the RNA-binding protein Lin28b. A large body of literature supports an instructive role of BCR signaling in B-1a cell development and lineage commitment, which is initiated only after signaling from an autoreactive BCR. While both fetal and adult hematopoiesis can generate B-1a cells, the contribution of adult hematopoiesis to the B-1a cell compartment is low under physiological conditions. We discuss several models that can reconcile the instructive role of BCR signaling with this fetal bias in B-1a cell development.

Figure 1. Distinct effects of autoreactive antigen receptors in fetal and adult lymphopoiesis

Fetal and neonatal lymphocytes expressing autoreactive antigen receptors seem to tolerate strong signaling, which may promote their efficient diversion to innate-like T or B cell lineages [36]. In contrast, adult autoreactive lymphocytes are efficiently eliminated by tolerance mechanisms such as negative selection, receptor editing or anergy induction.

Figure 2. Generation of autoreactive BCRs by premature Igk rearrangements in fetal pro-B cells

In the classical pathway of B cell development, pro-B cells experience strong IL-7R signaling, which activates the JAK/STAT pathway leading to active, phosphorylated (p) STAT5. Igk recombination is suppressed by pSTAT5 in IL-7R⁺ pro-B cells, which undergo VH-DJH recombination at the Igh locus, and is induced only after the pre-BCR transition in small IL-7R⁻ pre-B cells containing low pSTAT5 levels. In contrast, IL-7R/pSTAT5 signaling is low already in fetal and neonatal pro-B cells, leading to efficient Igk rearrangements concomitant with Igh recombination, which directly generates mature BCRs. If an autoreactive BCR is generated, it is stimulated by self-antigen (red dots), which results in proliferative cell expansion and commitment to the B-1a cell lineage by bypassing the pre-BCR stage. The model of the alternative developmental pathway is based on recently published data [44].

Figure 3. Clonal evolution of the BCR repertoire of B-1a cells throughout adult life

The schematic diagrams of the B-1a BCR repertoire in neonatal, young and adult mice are based on data obtained by high-throughput CDR3 sequencing of rearranged Igh transcripts [9]. Each rectangle represents a unique CDR3 sequence, and the size denotes the relative frequency (clone size) of an individual sequence. B-1a cell clones derived from FL HSCs are shown as filled colored rectangles, while B-1a cell clones originating from BM HSC are indicated by white rectangles.