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A plasma cell differentiation quality control ablates B cell clones with biallelic Ig rearrangements and truncated Ig production
Aberrantly rearranged immunoglobulin (Ig) alleles are frequent. They are usually considered sterile and innocuous as a result of nonsense-mediated mRNA decay. However, alternative splicing can yield internally deleted proteins from such nonproductively V(D)J-rearranged loci. We show that nonsense co...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710196/ https://www.ncbi.nlm.nih.gov/pubmed/26666261 http://dx.doi.org/10.1084/jem.20131511 |
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author | Srour, Nivine Chemin, Guillaume Tinguely, Aurélien Ashi, Mohamad Omar Oruc, Zéliha Péron, Sophie Sirac, Christophe Cogné, Michel Delpy, Laurent |
author_facet | Srour, Nivine Chemin, Guillaume Tinguely, Aurélien Ashi, Mohamad Omar Oruc, Zéliha Péron, Sophie Sirac, Christophe Cogné, Michel Delpy, Laurent |
author_sort | Srour, Nivine |
collection | PubMed |
description | Aberrantly rearranged immunoglobulin (Ig) alleles are frequent. They are usually considered sterile and innocuous as a result of nonsense-mediated mRNA decay. However, alternative splicing can yield internally deleted proteins from such nonproductively V(D)J-rearranged loci. We show that nonsense codons from variable (V) Igκ exons promote exon-skipping and synthesis of V domain-less κ light chains (ΔV-κLCs). Unexpectedly, such ΔV-κLCs inhibit plasma cell (PC) differentiation. Accordingly, in wild-type mice, rearrangements encoding ΔV-κLCs are rare in PCs, but frequent in B cells. Likewise, enforcing expression of ΔV-κLCs impaired PC differentiation and antibody responses without disturbing germinal center reactions. In addition, PCs expressing ΔV-κLCs synthesize low levels of Ig and are mostly found among short-lived plasmablasts. ΔV-κLCs have intrinsic toxic effects in PCs unrelated to Ig assembly, but mediated by ER stress–associated apoptosis, making PCs producing ΔV-κLCs highly sensitive to proteasome inhibitors. Altogether, these findings demonstrate a quality control checkpoint blunting terminal PC differentiation by eliminating those cells expressing nonfunctionally rearranged Igκ alleles. This truncated Ig exclusion (TIE) checkpoint ablates PC clones with ΔV-κLCs production and exacerbated ER stress response. The TIE checkpoint thus mediates selection of long-lived PCs with limited ER stress supporting high Ig secretion, but with a cost in terms of antigen-independent narrowing of the repertoire. |
format | Online Article Text |
id | pubmed-4710196 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-47101962016-07-11 A plasma cell differentiation quality control ablates B cell clones with biallelic Ig rearrangements and truncated Ig production Srour, Nivine Chemin, Guillaume Tinguely, Aurélien Ashi, Mohamad Omar Oruc, Zéliha Péron, Sophie Sirac, Christophe Cogné, Michel Delpy, Laurent J Exp Med Research Articles Aberrantly rearranged immunoglobulin (Ig) alleles are frequent. They are usually considered sterile and innocuous as a result of nonsense-mediated mRNA decay. However, alternative splicing can yield internally deleted proteins from such nonproductively V(D)J-rearranged loci. We show that nonsense codons from variable (V) Igκ exons promote exon-skipping and synthesis of V domain-less κ light chains (ΔV-κLCs). Unexpectedly, such ΔV-κLCs inhibit plasma cell (PC) differentiation. Accordingly, in wild-type mice, rearrangements encoding ΔV-κLCs are rare in PCs, but frequent in B cells. Likewise, enforcing expression of ΔV-κLCs impaired PC differentiation and antibody responses without disturbing germinal center reactions. In addition, PCs expressing ΔV-κLCs synthesize low levels of Ig and are mostly found among short-lived plasmablasts. ΔV-κLCs have intrinsic toxic effects in PCs unrelated to Ig assembly, but mediated by ER stress–associated apoptosis, making PCs producing ΔV-κLCs highly sensitive to proteasome inhibitors. Altogether, these findings demonstrate a quality control checkpoint blunting terminal PC differentiation by eliminating those cells expressing nonfunctionally rearranged Igκ alleles. This truncated Ig exclusion (TIE) checkpoint ablates PC clones with ΔV-κLCs production and exacerbated ER stress response. The TIE checkpoint thus mediates selection of long-lived PCs with limited ER stress supporting high Ig secretion, but with a cost in terms of antigen-independent narrowing of the repertoire. The Rockefeller University Press 2016-01-11 /pmc/articles/PMC4710196/ /pubmed/26666261 http://dx.doi.org/10.1084/jem.20131511 Text en © 2016 Srour et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Srour, Nivine Chemin, Guillaume Tinguely, Aurélien Ashi, Mohamad Omar Oruc, Zéliha Péron, Sophie Sirac, Christophe Cogné, Michel Delpy, Laurent A plasma cell differentiation quality control ablates B cell clones with biallelic Ig rearrangements and truncated Ig production |
title | A plasma cell differentiation quality control ablates B cell clones with biallelic Ig rearrangements and truncated Ig production |
title_full | A plasma cell differentiation quality control ablates B cell clones with biallelic Ig rearrangements and truncated Ig production |
title_fullStr | A plasma cell differentiation quality control ablates B cell clones with biallelic Ig rearrangements and truncated Ig production |
title_full_unstemmed | A plasma cell differentiation quality control ablates B cell clones with biallelic Ig rearrangements and truncated Ig production |
title_short | A plasma cell differentiation quality control ablates B cell clones with biallelic Ig rearrangements and truncated Ig production |
title_sort | plasma cell differentiation quality control ablates b cell clones with biallelic ig rearrangements and truncated ig production |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710196/ https://www.ncbi.nlm.nih.gov/pubmed/26666261 http://dx.doi.org/10.1084/jem.20131511 |
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