Activation induced deaminase in B cell fate decisions and lymphomagenesis

Abstract

Germinal centers (GC) are microstructures where B cells that have been activated by antigen can improve the affinity of their B cell receptors and differentiate into memory B cells or antibody (Ab) secreting plasma cells. GCs are the sites of secondary Ab diversification and underlie the mechanism of action of many vaccination strategies. Secondary Ab diversification comprise somatic hypermutation and class switch recombination, both of which are initiated by Activation Induced Deaminase (AID). However, AID can also target other regions in the genome, giving rise to mutations and chromosome translocations that can potentially lead to oncogenic transformation. In the first part of this Thesis, we have addressed the role of AID in the terminal differentiation of GC B cells. By combining single cell transcriptome and immunoglobulin clonal analysis in a mouse model that traces AID-experienced cells, we have identified a novel subset of late pre-plasmablast cells (L-prePB), which shares the strongest clonal relationships with plasmablasts (PBs). Mice lacking AID have various alterations in the size and expression profiles of GC transcriptional clusters. We have found that AID deficiency leads to a reduced proportion of L-prePB cells and severely impairs transitions between the L-prePB and the PB subsets. Thus, AID shapes the differentiation fate of GC B cells by enabling PB generation from a prePB state. In the second part of this Thesis, we assessed the role of AID in B cell lymphomagenesis by tracing AID expression in the λ-MYC model for Burkitt lymphoma. We found that λ-MYC mice show a block in B cell differentiation in the bone marrow, which associated with the premature expression of c-MYC and resulted in the generation of immature tumors. Unexpectedly, only a fraction of mature tumors contained GC-derived cells. Further, in this model, AID experienced lymphomas had better survival, presumably by increasing tumor immunogenicity. Our results suggest that, under specific contexts, AID can be onco-protective