It has been recognized for 40 years that the variable (diversity) joining [V(D)J] recombination-mediated assembly of diverse B and T lymphocyte antigen receptor (AgR) genes is not only essential for adaptive immunity, but also a risk for autoimmunity and lymphoid malignancies. Over the past few years, several studies have revealed that recombination-activating gene (RAG) endonuclease-induced DNA double-strand breaks (DSBs) transcend hazardous intermediates during antigen receptor gene assembly. RAG cleavage within the genomes of lymphocyte progenitors and immature lymphocytes regulates the expression of ubiquitous and lymphocyte-specific gene transcripts to control the differentiation and function of both adaptive and innate immune cell lineages. These unexpected discoveries raise important new questions that have broad implications for basic immunology research and the screening, diagnosis, and treatment of human immunological disease.

40 年来人们一直认识到，连接 [V(D)J] 重组介导的不同 B 和 T 淋巴细胞抗原受体 (AgR) 基因组装的变量（多样性）不仅对于适应性免疫至关重要，而且还存在以下风险：自身免疫和淋巴系统恶性肿瘤。过去几年，多项研究表明，重组激活基因 (RAG) 核酸内切酶诱导的 DNA 双链断裂 (DSB) 在抗原受体基因组装过程中超越了危险的中间体。淋巴细胞祖细胞和未成熟淋巴细胞基因组内的 RAG 裂解调节普遍存在的淋巴细胞特异性基因转录物的表达，以控制适应性和先天免疫细胞谱系的分化和功能。这些意想不到的发现提出了重要的新问题，对基础免疫学研究以及人类免疫疾病的筛查、诊断和治疗具有广泛的影响。