In:
The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 153.13-153.13
Abstract:
Innate-like B-1a B cells produce ‘natural’ antibodies (Abs) to neutralize pathogens and clear neo self-antigens, but the early selection mechanisms that shape their polyreactive repertoires are poorly understood. Fc receptor-like (Fcrl) genes encode surface regulatory proteins preferentially expressed by B cells. Here, we identified a B cell progenitor subset defined by FCRL6 expression, harboring emerging Ighv repertoire, migration, and differentiation properties conducive for natural Ab generation. Receptor-specific monoclonal antibodies identified subpopulations of FCRL6+ pro B cells in E18 fetal liver (FL), neonatal tissues, and adult bone marrow (BM). While it was absent on Hardy Fr. A cells, FCRL6 expression became evident in Fr. B, peaked in Fr. C, and declined in Fr. C′. By the Dorshkind scheme, FCRL6 marked subsets of B-1P and pro B cells in the FL and BM, but was not detected on B-2P cells. 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. Similar features were apparent among B-1a and chronic lymphocytic leukemia (CLL) Ighv 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.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.204.Supp.153.13
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2020
detail.hit.zdb_id:
1475085-5
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