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 : Immunoglobulin RNA
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Article dans une revue
Journal of Experimental Medicine, Rockefeller University Press, 2016, 213 (1), pp.109-122. 〈10.1084/jem.20131511〉
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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, Rockefeller University Press, 2016, 213 (1), pp.109-122. 〈10.1084/jem.20131511〉. 〈hal-01501807〉

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