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, 5 (5), 1118-31

AID-induced Remodeling of Immunoglobulin Genes and B Cell Fate


AID-induced Remodeling of Immunoglobulin Genes and B Cell Fate

Brice Laffleur et al. Oncotarget.


Survival and phenotype of normal and malignant B lymphocytes are critically dependent on constitutive signals by the B cell receptor (BCR) for antigen. In addition, either antigen ligation of the BCR or various mitogenic stimuli result in B cell activation and induction of activation-induced deaminase (AID). AID activity can in turn mediate somatic hypermutation (SHM) of immunoglobulin (Ig) V regions and also deeply remodel the Ig heavy chain locus through class switch recombination (CSR) or locus suicide recombination (LSR). In addition to changes linked to affinity for antigen, modifying the class/isotype (i.e. the structure and function) of the BCR or suddenly deleting BCR expression also modulates the fate of antigen-experienced B cells.


Figure 1
Figure 1. AID targeting of the IgH locus
Upon B cell activation, induced AID expression remodels Ig gene V regions through SHM or eventually gene conversion (GCV), generating B cell receptors of improved affinity for antigen. B cells, in parallel or later, diversify the BCR class through class switch recombination (CSR). Locus suicide recombination (LSR) eventually joins the switch μ region (Sμ) with one of the like-switch (LS) repetitive regions located within the 3' regulatory region (3'RR), then deletes all IgH constant genes and switches off BCR expression, thus leading to B cell death.
Figure 2
Figure 2. BCR class and signaling cascades
Some specific functions of the various BCR classes are indicated (left). Specific transcription factors expressed before CSR to a given class (and eventually after CSR) are mentioned (middle). Each BCR class is represented as a membrane Ig associated with the Igɑ/ß signaling modules (right). The three amino acids (KVK) of the IgM and IgD BCR and longer intra-cytoplasmic tails of other classes are shown. The main signaling proteins and pathways that are common or most likely specific to these BCR classes are represented (right).
Figure 3
Figure 3. AID-modulation of B cell fate in the context of lymphoid tissues
After V(D)J recombination and IgM expression, recently emerged B cells circulate as transitional cells and can be committed to various compartments depending upon BCR signalling (Notch2 expression and weak BCR tonic signaling commit B cells to a marginal zone fate). After maturation into IgM+, IgD+ cells, naïve B cells encounter T-dependent Ag and undergo cognate interactions with pre-TFH cells. B cells then initially activate in extra-follicular foci and differentiate into short-lived plasma cells, or participate with TFH in the formation of GCs where their BCRs will be deeply remodeled by SHM (mostly in the proliferating dark zone) or CSR (mostly in the GC light zone), or eventually LSR. The GC reaction will yield both memory cells and plasma cells, some being long-lived and surviving after their migration to several protective niches (spleen red pulp, bone marrow, MALT…).

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