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

Abstract : 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.
Keywords : RNA Immunoglobulin
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Soumis le : mardi 4 avril 2017 - 15:50:58
Dernière modification le : dimanche 26 juin 2022 - 13:22:27
Archivage à long terme le : : mercredi 5 juillet 2017 - 18:10:57


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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⟩



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