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Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth
Affinity maturation depends on how efficiently germinal centers (GCs) positively select B cells in the light zone (LZ). Positively selected GC B cells recirculate between LZs and dark zones (DZs) and ultimately differentiate into plasmablasts (PBs) and memory B cells (MBCs). Current understanding of...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812803/ https://www.ncbi.nlm.nih.gov/pubmed/33419925 http://dx.doi.org/10.1073/pnas.2016425118 |
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author | Nakagawa, Rinako Toboso-Navasa, Amparo Schips, Marta Young, George Bhaw-Rosun, Leena Llorian-Sopena, Miriam Chakravarty, Probir Sesay, Abdul Karim Kassiotis, George Meyer-Hermann, Michael Calado, Dinis Pedro |
author_facet | Nakagawa, Rinako Toboso-Navasa, Amparo Schips, Marta Young, George Bhaw-Rosun, Leena Llorian-Sopena, Miriam Chakravarty, Probir Sesay, Abdul Karim Kassiotis, George Meyer-Hermann, Michael Calado, Dinis Pedro |
author_sort | Nakagawa, Rinako |
collection | PubMed |
description | Affinity maturation depends on how efficiently germinal centers (GCs) positively select B cells in the light zone (LZ). Positively selected GC B cells recirculate between LZs and dark zones (DZs) and ultimately differentiate into plasmablasts (PBs) and memory B cells (MBCs). Current understanding of the GC reaction presumes that cMyc-dependent positive selection of LZ B cells is a competitive affinity-dependent process; however, this cannot explain the production of GC-derived lower-affinity MBCs or retention of GC B cells with varied affinities. Here, by combining single-cell/bulk RNA sequencing and flow cytometry, we identified and characterized temporally and functionally distinct positively selected cMyc(+) GC B cell subpopulations. cMyc(+) LZ B cell subpopulations enriched with either higher- or lower-affinity cells diverged soon after permissive positive selection. The former subpopulation contained PB precursors, whereas the latter comprised less proliferative MBC precursors and future DZ entrants. The overall affinity of future DZ entrants was enhanced in the LZ through preferential proliferation of higher-affinity cells. Concurrently, lower-affinity cells were retained in GCs and protected from apoptosis. These findings redefine positive selection as a dynamic process generating three distinct B cell fates and elucidate how positive selection ensures clonal diversity for broad protection. |
format | Online Article Text |
id | pubmed-7812803 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-78128032021-01-28 Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth Nakagawa, Rinako Toboso-Navasa, Amparo Schips, Marta Young, George Bhaw-Rosun, Leena Llorian-Sopena, Miriam Chakravarty, Probir Sesay, Abdul Karim Kassiotis, George Meyer-Hermann, Michael Calado, Dinis Pedro Proc Natl Acad Sci U S A Biological Sciences Affinity maturation depends on how efficiently germinal centers (GCs) positively select B cells in the light zone (LZ). Positively selected GC B cells recirculate between LZs and dark zones (DZs) and ultimately differentiate into plasmablasts (PBs) and memory B cells (MBCs). Current understanding of the GC reaction presumes that cMyc-dependent positive selection of LZ B cells is a competitive affinity-dependent process; however, this cannot explain the production of GC-derived lower-affinity MBCs or retention of GC B cells with varied affinities. Here, by combining single-cell/bulk RNA sequencing and flow cytometry, we identified and characterized temporally and functionally distinct positively selected cMyc(+) GC B cell subpopulations. cMyc(+) LZ B cell subpopulations enriched with either higher- or lower-affinity cells diverged soon after permissive positive selection. The former subpopulation contained PB precursors, whereas the latter comprised less proliferative MBC precursors and future DZ entrants. The overall affinity of future DZ entrants was enhanced in the LZ through preferential proliferation of higher-affinity cells. Concurrently, lower-affinity cells were retained in GCs and protected from apoptosis. These findings redefine positive selection as a dynamic process generating three distinct B cell fates and elucidate how positive selection ensures clonal diversity for broad protection. National Academy of Sciences 2021-01-12 2021-01-08 /pmc/articles/PMC7812803/ /pubmed/33419925 http://dx.doi.org/10.1073/pnas.2016425118 Text en Copyright © 2021 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Nakagawa, Rinako Toboso-Navasa, Amparo Schips, Marta Young, George Bhaw-Rosun, Leena Llorian-Sopena, Miriam Chakravarty, Probir Sesay, Abdul Karim Kassiotis, George Meyer-Hermann, Michael Calado, Dinis Pedro Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth |
title | Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth |
title_full | Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth |
title_fullStr | Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth |
title_full_unstemmed | Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth |
title_short | Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth |
title_sort | permissive selection followed by affinity-based proliferation of gc light zone b cells dictates cell fate and ensures clonal breadth |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812803/ https://www.ncbi.nlm.nih.gov/pubmed/33419925 http://dx.doi.org/10.1073/pnas.2016425118 |
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