Abstract
B-1a cells produce “natural” antibodies (Abs) to neutralize pathogens and clear neo self-antigens, but the fundamental selection mechanisms that shape their polyreactive repertoires are poorly understood. Here, we identified a B cell progenitor subset defined by Fc receptor-like 6 (FCRL6) expression, harboring innate-like defense, migration, and differentiation properties conducive for natural Ab generation. Compared to FCRL6− pro B cells, the repressed mitotic, DNA damage repair, and signaling activity of FCRL6+ progenitors, yielded VH repertoires with biased distal Ighv segment accessibility, constrained diversity, and hydrophobic and charged CDR-H3 sequences. Beyond nascent autoreactivity, VH11 productivity, which predominates phosphatidylcholine-specific B-1a B cell receptors (BCRs), was higher for FCRL6+ cells as was pre-BCR formation, which was required for Myc induction and VH11, but not VH12, B-1a development. Thus, FCRL6 revealed unexpected heterogeneity in the developmental origins, regulation, and selection of natural Abs at the pre-BCR checkpoint with implications for autoimmunity and lymphoproliferative disorders.
Highlights
B-1 B cells, and B-1a cells that express CD5, are the primary source of “natural” antibodies (Abs) whose poly/autoreactive features provide homeostatic protection against bacterial and viral pathogens [1,2,3]
Fc receptor-like 6 (FCRL6) is confined to natural killer (NK) and T cells in humans [47], by flow cytometry analysis from adult BALB/cJ bone marrow (BM), FCRL6 was restricted to early stage B cells (Supplementary Figure 1C and data not shown)
FCRL6 distinguished a subset of B cell progenitors that is evident from embryogenesis through adulthood and appears to be conserved throughout ontogeny
Summary
B-1 B cells, and B-1a cells that express CD5, are the primary source of “natural” antibodies (Abs) whose poly/autoreactive features provide homeostatic protection against bacterial and viral pathogens [1,2,3]. The Ab repertoires of B-1a cells have a biased composition. Due to a lack of Tdt mediated Naddition during fetal life [9, 10], they generate germline-related Abs encoding CDR-H3 segments that are more hydrophobic than B-2 repertoires [11, 12]. Splenic marginal zone (MZ) B cells possess innate-like defense properties and fetalrelated VH repertoires enriched in charged CDR-H3 segments [11, 13, 14]. The propensity to generate autoreactive Abs has implicated innate-like MZ and B-1 B cells in the pathogenesis of autoimmunity (AI) and malignancy, including the most common leukemia in Western countries, chronic lymphocytic leukemia (CLL) [15,16,17]
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