Division of Hematology and Oncology, Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA.
Science. 2023 Jan 20;379(6629):eabj7412. doi: 10.1126/science.abj7412.
Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts. This effect was conferred by a small shift in MYC protein induction kinetics but resulted in aggressive invasive lymphomas, which in humans are linked to dire clinical outcomes. Our findings reveal a delicate evolutionary trade-off between natural selection of B cells to provide immunity and potentially dangerous features that recall the more competitive nature of unicellular organisms.
多细胞生命需要细胞之间的利他合作。适应性免疫系统是一个显著的例外，其中生发中心 B 细胞在竞争有限的阳性选择信号时竞争激烈。通过研究原发性人类淋巴瘤和开发新的小鼠模型，我们发现影响的突变破坏了一个关键的免疫守门员机制，该机制在抗体亲和力成熟过程中严格限制 B 细胞的适应性。该机制将生发中心 B 细胞转化为超级竞争者，使其迅速超越正常细胞。这种效应是由 MYC 蛋白诱导动力学的微小变化引起的，但导致侵袭性淋巴瘤，在人类中与可怕的临床结果相关。我们的发现揭示了 B 细胞提供免疫和潜在危险特征之间的微妙进化权衡，这些特征让人联想到单细胞生物的更具竞争力的本质。
