TY - JOUR
T1 - A plasma cell differentiation quality control ablates B cell clones with biallelic Ig rearrangements and truncated Ig production
AU - Srour, Nivine
AU - Chemin, Guillaume
AU - Tinguely, Aurélien
AU - Ashi, Mohamad Omar
AU - Oruc, Zéliha
AU - Péron, Sophie
AU - Sirac, Christophe
AU - Cogné, Michel
AU - Delpy, Laurent
N1 - Publisher Copyright:
© 2016 Srour et al.
PY - 2016/1/11
Y1 - 2016/1/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84961176227&partnerID=8YFLogxK
U2 - 10.1084/jem.20131511
DO - 10.1084/jem.20131511
M3 - Article
C2 - 26666261
AN - SCOPUS:84961176227
SN - 0022-1007
VL - 213
SP - 109
EP - 122
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 1
ER -