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Fig. 2. A Truncated Immunoglobulin Exclusion (TIE) checkpoint during terminal plasma cell differentiation. (Top) Schematic structure of the Igκ locus showing various classes of V–J rearrangements. In-frame and out-of-frame VJ junctions with the position of PTCs from the latter are depicted. Any VJ recombination involving mouse Jκ1 segments can lead to the appearance of PTCs in the last constant exon (Cκ). For other Jκ segments, the addition of 1 nucleotide (nt) (i.e., 3n + 1 nt) at the VJ junction also leads to the appearance of a PTC in the Cκ exon, whereas the addition of 2 nt (i.e. 3n + 2 nt) creates a PTC at the end of the variable (V) exon, 3nt upstream the exon-exon junction (50). (Middle) Whereas nonsense-associated altered splicing (NAS) is not activated by the presence of a PTC within the Cκ exon (CPTC class), PTCs in the V exon (VPTC class) can strongly promote exon skipping and translation of V domain-less κ light chains (ΔV-κLCs) (5, 16). (Bottom) The production of ΔV-κLCs is innocuous in B cells. However, it provokes endoplasmic reticulum (ER) stress-associated apoptosis in plasma cells (PCs), precluding their differentiation as long-lived PCs. Overall, significant numbers of PCs harboring biallelic VJ recombination in a VPTC/VJ+ configuration at the Igκ locus are eliminated through the activation of a Truncated Immunoglobulin Exclusion (TIE) checkpoint (16). The TIE checkpoint exhibits dual effects on antibody responses. On one hand, its activation blunts the PC repertoire that can emerge from mature B cells, thus limiting the extent of antibody responses. On the other hand, the TIE-checkpoint favors the selection of long-lived PCs with limited basal ER stress that supports further elevation of Ig secretion. GL: germline; VJ+: productively-recombined Igκ allele; VPTC: nonproductively-recombined Igκ allele harboring a PTC within the V exon; CPTC: nonproductively-recombined Igκ allele harboring a PTC within the Cκ exon.
BMB Reports 2019;52:671~678 https://doi.org/10.5483/BMBRep.2019.52.12.232
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