| First Author | Srour N | Year | 2016 |
| Journal | J Exp Med | Volume | 213 |
| Issue | 1 | Pages | 109-22 |
| PubMed ID | 26666261 | Mgi Jnum | J:232596 |
| Mgi Id | MGI:5779609 | Doi | 10.1084/jem.20131511 |
| Citation | Srour N, et al. (2016) A plasma cell differentiation quality control ablates B cell clones with biallelic Ig rearrangements and truncated Ig production. J Exp Med 213(1):109-22 |
| abstractText | 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) Igkappa exons promote exon-skipping and synthesis of V domain-less kappa light chains (DeltaV-kappaLCs). Unexpectedly, such DeltaV-kappaLCs inhibit plasma cell (PC) differentiation. Accordingly, in wild-type mice, rearrangements encoding DeltaV-kappaLCs are rare in PCs, but frequent in B cells. Likewise, enforcing expression of DeltaV-kappaLCs impaired PC differentiation and antibody responses without disturbing germinal center reactions. In addition, PCs expressing DeltaV-kappaLCs synthesize low levels of Ig and are mostly found among short-lived plasmablasts. DeltaV-kappaLCs have intrinsic toxic effects in PCs unrelated to Ig assembly, but mediated by ER stress-associated apoptosis, making PCs producing DeltaV-kappaLCs highly sensitive to proteasome inhibitors. Altogether, these findings demonstrate a quality control checkpoint blunting terminal PC differentiation by eliminating those cells expressing nonfunctionally rearranged Igkappa alleles. This truncated Ig exclusion (TIE) checkpoint ablates PC clones with DeltaV-kappaLCs 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. |
