A plasma cell differentiation quality control ablates B cell clones with biallelic Ig rearrangements and truncated Ig production - Université de Limoges Accéder directement au contenu
Article Dans Une Revue Journal of Experimental Medicine Année : 2016

A plasma cell differentiation quality control ablates B cell clones with biallelic Ig rearrangements and truncated Ig production

Résumé

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.

Mots clés

Domaines

Immunologie
Fichier principal
Vignette du fichier
109.full.pdf (2.2 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte
Loading...

Dates et versions

hal-01501807 , version 1 (04-04-2017)

Identifiants

Citer

Nivine Srour, Guillaume Chemin, Aurélien Tinguely, Mohamad Omar Ashi, Zéliha Oruc, et al.. A plasma cell differentiation quality control ablates B cell clones with biallelic Ig rearrangements and truncated Ig production. Journal of Experimental Medicine, 2016, 213 (1), pp.109-122. ⟨10.1084/jem.20131511⟩. ⟨hal-01501807⟩
167 Consultations
192 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More