Cvijović Ivana, Swift Michael, Quake Stephen R
Department of Applied Physics, Stanford University, Stanford, CA 94305.
Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2025 Mar 4;122(9):e2406474122. doi: 10.1073/pnas.2406474122. Epub 2025 Feb 28.
B cells generate pathogen-specific antibodies and play an essential role in providing adaptive protection against infection. Antibody genes are modified in evolutionary processes acting on the B cell populations within an individual. These populations proliferate, differentiate, and migrate to long-term niches in the body. However, the dynamics of these processes in the human immune system are primarily inferred from mouse studies. We addressed this gap by sequencing the antibody repertoire and transcriptomes from single B cells in four immune-rich tissues from six individuals. We find that B cells descended from the same pre-B cell ("lineages") often colocalize within the same tissue, with the bone marrow harboring the largest excess of lineages without representation in other tissues. Within lineages, cells with different levels of somatic hypermutation are uniformly distributed among tissues and functional states. This suggests that the relative probabilities of localization and differentiation outcomes change negligibly during affinity maturation, and quantitatively agrees with a simple dynamical model of B cell differentiation. While lineages strongly colocalize, we find individual B cells nevertheless appear to make independent differentiation decisions. Proliferative antibody-secreting cells, however, deviate from these global patterns. These cells are often clonally expanded, their clones appear universally distributed among all sampled organs, and form lineages with an excess of cells of the same type. Collectively, our findings show the limits of peripheral blood monitoring of the immune repertoire, and provide a probabilistic model of the dynamics of antibody memory formation in humans.
B细胞产生病原体特异性抗体，并在提供针对感染的适应性保护方面发挥重要作用。抗体基因在作用于个体内B细胞群体的进化过程中发生修饰。这些群体增殖、分化并迁移到体内的长期微环境中。然而，这些过程在人类免疫系统中的动态变化主要是从小鼠研究中推断出来的。我们通过对来自6名个体的4个富含免疫细胞的组织中的单个B细胞的抗体库和转录组进行测序，填补了这一空白。我们发现，来自同一个前B细胞（“谱系”）的B细胞通常在同一组织内共定位，骨髓中存在着在其他组织中没有的大量谱系。在谱系内，具有不同体细胞超突变水平的细胞在组织和功能状态中均匀分布。这表明，在亲和力成熟过程中，定位和分化结果的相对概率变化可以忽略不计，并且在定量上与B细胞分化的简单动力学模型一致。虽然谱系强烈共定位，但我们发现单个B细胞似乎仍然做出独立的分化决定。然而，增殖性抗体分泌细胞偏离了这些全局模式。这些细胞通常发生克隆性扩增，它们的克隆似乎普遍分布在所有采样器官中，并形成具有过量相同类型细胞的谱系。总的来说，我们的研究结果显示了免疫库外周血监测的局限性，并提供了人类抗体记忆形成动力学的概率模型。
