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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...

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Autores principales: Srour, Nivine, Chemin, Guillaume, Tinguely, Aurélien, Ashi, Mohamad Omar, Oruc, Zéliha, Péron, Sophie, Sirac, Christophe, Cogné, Michel, Delpy, Laurent
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2016
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.
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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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