RT Journal Article
SR Electronic
T1 Fc receptor-like 6 (FCRL6) defines pre-BCR dependent and independent pathways of natural antibody selection
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 667345
DO 10.1101/667345
A1 Kazuhito Honjo
A1 Woong-Jai Won
A1 Rodney G. King
A1 Lara Ianov
A1 David K. Crossman
A1 Juliet L. Easlick
A1 Mikhail A. Shakhmatov
A1 Mohamed Khass
A1 Andre M. Vale
A1 Robert P. Stephan
A1 Ran Li
A1 Randall S. Davis
YR 2019
UL http://biorxiv.org/content/early/2019/06/11/667345.abstract
AB 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.