@article{c12a6c5364864577ae3434d54848f515,
title = "Receptor editing constrains development of phosphatidyl choline-specific B cells in VH12-transgenic mice",
abstract = "B1 B cells reactive to phosphatidyl choline (PtC) exhibit restricted immunoglobulin heavy chain (HC) and light chain (LC) combinations, exemplified by VH12/Vκ4/5H. Two checkpoints are thought to focus PtC+ B cell maturation in VH12-transgenic mice (VH12 mice): V-J rearrangements encoding a “permissive” LC capable of VH12 HC pairing are selected first, followed by positive selection based on PtC binding, often requiring LC receptor editing to salvage PtC− B cells and acquire PtC reactivity. However, evidence obtained from breeding VH12 mice to editing-defective dnRAG1 mice and analyzing LC sequences from PtC+ and PtC− B cell subsets instead suggests that receptor editing functions after initial positive selection to remove PtC+ B cells in VH12 mice. This offers a mechanism to constrain natural, polyreactive B cells to limit their frequency. Sequencing also reveals occasional in-frame hybrid LC genes, reminiscent of type 2 gene replacement, that, testing suggests, arise via a recombination-activating gene (RAG)-independent mechanism.",
author = "Worth, {Alexandra N.} and Palmer, {Victoria L.} and Schabla, {N. Max} and Perry, {Greg A.} and Fraser-Philbin, {Anna N.} and Swanson, {Patrick C.}",
note = "Funding Information: The authors thank the Creighton University RadLab for configuring the server used for this study. The authors also thank Dr. M. Lieber for providing pEBB RAG expression constructs and Dr. Rob Todd and Dr. Anna Selmecki for valuable assistance and suggestions during LC sequencing protocol development. This work was supported by grants to P.C.S. from the National Institutes of Health (NIH) (R21AI119829 and R21AI159127) and the George F. Haddix President's Faculty Research Fund and by revenue from Nebraska's excise tax on cigarettes awarded to Creighton University through the Nebraska Department of Health & Human Services (DHHS). NIH funding to support research laboratory construction (C06RR017417), the Creighton University Animal Resource Facility (G20RR024001), and acquisition of the GE Healthcare Typhoon 9410 Variable Mode Imager (S10RR027352) and Bio-Rad ZE5 Cell Analyzer (3R01GM102487-03S1) used in this study is gratefully acknowledged. This publication's contents represent the view(s) of the author(s) and do not necessarily represent the official views of the State of Nebraska, DHHS, or the NIH. Conceptualization, A.N.W. and P.C.S.; methodology, A.N.W. N.M.S. V.L.P. G.A.P. and P.C.S.; software, A.N.W.; investigation, A.N.W. N.M.S. V.L.P. G.A.P. A.N.F.-P. and P.C.S.; writing – original draft, A.N.W. and P.C.S.; writing – review & editing, A.N.W. N.M.S. V.L.P. A.N.F.-P. G.A.P. and P.C.S.; visualization, A.N.W. and P.C.S.; funding acquisition, P.C.S.; supervision, P.C.S. The authors declare no competing interests. Funding Information: The authors thank the Creighton University RadLab for configuring the server used for this study. The authors also thank Dr. M. Lieber for providing pEBB RAG expression constructs and Dr. Rob Todd and Dr. Anna Selmecki for valuable assistance and suggestions during LC sequencing protocol development. This work was supported by grants to P.C.S. from the National Institutes of Health (NIH) ( R21AI119829 and R21AI159127 ) and the George F. Haddix President{\textquoteright}s Faculty Research Fund and by revenue from Nebraska{\textquoteright}s excise tax on cigarettes awarded to Creighton University through the Nebraska Department of Health & Human Services (DHHS) . NIH funding to support research laboratory construction ( C06RR017417 ), the Creighton University Animal Resource Facility ( G20RR02400 1), and acquisition of the GE Healthcare Typhoon 9410 Variable Mode Imager ( S10RR027352 ) and Bio-Rad ZE5 Cell Analyzer (3R01GM102487-03S1) used in this study is gratefully acknowledged. This publication{\textquoteright}s contents represent the view(s) of the author(s) and do not necessarily represent the official views of the State of Nebraska, DHHS, or the NIH. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = jun,
day = "14",
doi = "10.1016/j.celrep.2022.110899",
language = "English (US)",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}