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

Nivine Srour, Guillaume Chemin, Aurélien Tinguely, Mohamad Omar Ashi, Zéliha Oruc, Sophie Péron, Christophe Sirac, Michel Cogné, Laurent Delpy

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

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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) IgΔ 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 IgΔ 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.

langue originaleAnglais
Pages (de - à)109-122
Nombre de pages14
journalJournal of Experimental Medicine
Volume213
Numéro de publication1
Les DOIs
étatPublié - 11 janv. 2016
Modification externeOui

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