Sequence-Intrinsic Mechanisms that Target AID Mutational Outcomes on Antibody Genes.
Sequence-Intrinsic Mechanisms that Target AID Mutational Outcomes on Antibody Genes.
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DOI：
10.1016/j.cell.2015.10.042
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发表时间：
2015-11-19
期刊：
影响因子：
64.5
通讯作者：
Alt FW
中科院分区：
文献类型：
--
作者：
Yeap LS;Hwang JK;Du Z;Meyers RM;Meng FL;Jakubauskaitė A;Liu M;Mani V;Neuberg D;Kepler TB;Wang JH;Alt FW
在活化的B淋巴细胞中，AID启动抗体可变（V）外显子体细胞超突变（SHM）以在生发中心（GC）中进行亲和力成熟，并启动IgH开关（S）区DNA断裂（DSB）以进行类别转换重组（CSR）。为了解决长期存在的问题，我们已经开发了一种体内测定来研究替代V外显子的乘客序列的AIDS靶向。首先，我们发现AID以相似的频率靶向V外显子和S区乘客内的SHM热点，并且正常的SHM过程经常产生缺失，表明SHM和CSR采用相同的机制。其次，AID使GC B细胞中不同非免疫球蛋白乘客的靶点发生突变，其水平与V外显子的水平相似，明确确定V外显子位置为SHM的“特权”。最后，派伊尔斑GC B细胞产生在选择亲和力成熟之前高度突变的V外显子的库。我们讨论这些发现的影响，利用抗体多样化机制。
In activated B lymphocytes, AID initiates antibody variable (V) exon somatic hypermutation (SHM) for affinity maturation in germinal centers (GCs) and IgH switch (S) region DNA breaks (DSBs) for class-switch recombination (CSR). To resolve long-standing questions, we have developed an in vivo assay to study AID-targeting of passenger sequences replacing a V exon. First, we find AID targets SHM hotspots within V exon and S region passengers at similar frequencies and that the normal SHM process frequently generates deletions, indicating that SHM and CSR employ the same mechanism. Second, AID mutates targets in diverse non-Ig passengers in GC B cells at levels similar to those of V exons, definitively establishing the V exon location as "privileged" for SHM. Finally, Peyer's patch GC B cells generate a reservoir of V exons that are highly mutated before selection for affinity maturation. We discuss implications of these findings for harnessing antibody diversification mechanisms.