Lineage tracing reveals B cell antibody class switching is stochastic, cell-autonomous, and tuneable.
Lineage tracing reveals B cell antibody class switching is stochastic, cell-autonomous, and tuneable.
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DOI：
10.1016/j.immuni.2022.08.004
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发表时间：
2022-09
期刊：
影响因子：
32.4
通讯作者：
M. Horton;Hochan Cheon;K. Duffy;Daniel V. Brown;S. Naik;Carolina Alvarado;J. Groom;S. Heinzel;P. Hodgkin
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文献类型：
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作者：
M. Horton;Hochan Cheon;K. Duffy;Daniel V. Brown;S. Naik;Carolina Alvarado;J. Groom;S. Heinzel;P. Hodgkin
为了优化对病原体的免疫，B淋巴细胞产生具有功能多样的抗体同种型的浆细胞。通过在分化的B细胞克隆中对单个细胞进行谱系追踪，我们确定了离散命运控制机制的遗传性，从而为B细胞命运调控的一般数学模型提供信息。创始人细胞高度影响克隆浆细胞的命运，而类转换重组（CSR）是多样化的克隆内。反过来，这些CSR模式是由激活诱导的胞苷脱氨酶（AID）和IgH种系转录（GLT）的独立全或无表达引起的，后者在每次细胞分裂后随机重新表达。基于这些分子转换规则的随机模型准确地预测了体外和体内免疫应答过程中不同条件下的抗体转换结果。因此，功能多样的抗体类型的产生遵循自主细胞编程的规则，其可以被调整和建模用于合理控制抗体类别以获得潜在的治疗益处。
To optimize immunity to pathogens, B lymphocytes generate plasma cells with functionally diverse antibody isotypes. By lineage tracing single cells within differentiating B cell clones, we identified the heritability of discrete fate controlling mechanisms to inform a general mathematical model of B cell fate regulation. Founder cells highly influenced clonal plasma-cell fate, whereas class switch recombination (CSR) was variegated within clones. In turn, these CSR patterns resulted from independent all-or-none expression of bothactivation-induced cytidine deaminase(AID) andIgHgermline transcription (GLT), with the latter being randomly re-expressed after each cell division. A stochastic model premised on these molecular transition rules accurately predicted antibody switching outcomes under varied conditionsin vitroand during an immune responsein vivo. Thus, the generation of functionally diverse antibody types follows rules of autonomous cellular programming that can be adapted and modeled for the rational control of antibody classes for potential therapeutic benefit.