title: 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.
authors.affiliation: Centre National de la Recherche Scientifique UMR 7276, Université de Limoges, 87000 Limoges, France.
authors.forename: Nivine
authors.initials: N
authors.lastname: Srour
authors.affiliation: Centre National de la Recherche Scientifique UMR 7276, Université de Limoges, 87000 Limoges, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Chemin
authors.affiliation: Centre National de la Recherche Scientifique UMR 7276, Université de Limoges, 87000 Limoges, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Tinguely
authors.affiliation: Centre National de la Recherche Scientifique UMR 7276, Université de Limoges, 87000 Limoges, France.
authors.forename: Mohamad Omar
authors.initials: MO
authors.lastname: Ashi
authors.affiliation: Centre National de la Recherche Scientifique UMR 7276, Université de Limoges, 87000 Limoges, France.
authors.forename: Zéliha
authors.initials: Z
authors.lastname: Oruc
authors.affiliation: Centre National de la Recherche Scientifique UMR 7276, Université de Limoges, 87000 Limoges, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Péron
authors.affiliation: Centre National de la Recherche Scientifique UMR 7276, Université de Limoges, 87000 Limoges, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Sirac
authors.affiliation: Centre National de la Recherche Scientifique UMR 7276, Université de Limoges, 87000 Limoges, France Institut Universitaire de France, Université de Limoges, 87000 Limoges, France laurent.delpy@unilim.fr michel.cogne@unilim.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Cogné
authors.affiliation: Centre National de la Recherche Scientifique UMR 7276, Université de Limoges, 87000 Limoges, France laurent.delpy@unilim.fr michel.cogne@unilim.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Delpy
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D018389:Codon, Nonsense; D059865:Endoplasmic Reticulum Stress; D005091:Exons; D015322:Gene Rearrangement, B-Lymphocyte; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007136:Immunoglobulins / Q000235:genetics*; D051379:Mice; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D018389:Codon, Nonsense; D007135:Immunoglobulin Variable Region; D007136:Immunoglobulins