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

作者：Srour Nivine; Chemin Guillaume; Tinguely Aurelien; Ashi Mohamad Omar; Oruc Zeliha; Peron Sophie; Sirac Christophe; Cogne Michel; Delpy Laurent^*

来源：Journal of Experimental Medicine, 2016, 213(1): 109-122.

DOI：10.1084/jem.20131511

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) Ig kappa exons promote exon-skipping and synthesis of V domain-less. light chains (Delta V-kappa LCs). Unexpectedly, such Delta V-kappa LCs inhibit plasma cell (PC) differentiation. Accordingly, in wild-type mice, rearrangements encoding Delta V-kappa LCs are rare in PCs, but frequent in B cells. Likewise, enforcing expression of Delta V-kappa LCs impaired PC differentiation and antibody responses without disturbing germinal center reactions. In addition, PCs expressing Delta V-kappa LCs synthesize low levels of Ig and are mostly found among short-lived plasmablasts. Delta V-kappa LCs have intrinsic toxic effects in PCs unrelated to Ig assembly, but mediated by ER stress-associated apoptosis, making PCs producing Delta V-kappa LCs highly sensitive to proteasome inhibitors. Altogether, these findings demonstrate a quality control checkpoint blunting terminal PC differentiation by eliminating those cells expressing nonfunctionally rearranged Ig. alleles. This truncated Ig exclusion (TIE) checkpoint ablates PC clones with Delta V-kappa LCs 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.

• 出版日期2016-1-11