AUTHOR=Honjo Kazuhito , Won Woong-Jai , King Rodney G. , Ianov Lara , Crossman David K. , Easlick Juliet L. , Shakhmatov Mikhail A. , Khass Mohamed , Vale Andre M. , Stephan Robert P. , Li Ran , Davis Randall S. 

TITLE=Fc Receptor-Like 6 (FCRL6) Discloses Progenitor B Cell Heterogeneity That Correlates With Pre-BCR Dependent and Independent Pathways of Natural Antibody Selection

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00082

DOI=10.3389/fimmu.2020.00082

ISSN=1664-3224

ABSTRACT=<p>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<sup>−</sup> pro B cells, the repressed mitotic, DNA damage repair, and signaling activity of FCRL6<sup>+</sup> progenitors, yielded V<sub>H</sub> repertoires with biased distal <italic>Ighv</italic> segment accessibility, constrained diversity, and hydrophobic and charged CDR-H3 sequences. Beyond nascent autoreactivity, V<sub>H</sub>11 productivity, which predominates phosphatidylcholine-specific B-1a B cell receptors (BCRs), was higher for FCRL6<sup>+</sup> cells as was pre-BCR formation, which was required for Myc induction and V<sub>H</sub>11, but not V<sub>H</sub>12, 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.</p>