体细胞基因突变在体内发生，原因是在正常DNA合成过程中自发发生的复制错误或在胚胎发育过程中内源性或外源性诱变剂损伤DNA的模板上进行复制而发生的。原则上，人体内突变细胞频率的变化反映了暴露于外源性或内源性DNA损伤刺激的变化，其他条件相同。然而，越来越清楚的是，人体内的体细胞突变有更广泛的解释。例如，淋巴细胞中的突变提供了有价值的探针，用于体内细胞和分子过程的研究，提供了在自身免疫性和传染性疾病、移植接受者、夜间阵发性血红蛋白尿症（PNH）和癌症中恶性细胞群扩增的鉴定。针对X染色体次黄嘌呤鸟嘌呤磷酸核糖转移酶（HPRT）基因的突变检测已获得广泛接受，因为可恢复到可行的突变细胞用于分子和其他分析。尽管HPRT T细胞检测的主要应用仍是人口监测，但在患有免疫过程的个体中富集的激活T细胞在突变分数中证明了替代选择的实用性，这种方法使用体细胞突变作为在免疫过程下潜在的T细胞增殖的代理标记来研究具有免疫特征的临床疾病。本文回顾了涵盖多种临床情况的研究。尽管HPRT突变系统在验证替代选择方面具有历史意义，但现在有其他突变和方法用于识别免疫活性的T细胞。这些方法受到审查，并提供了策略来扩展未来研究中的替代选择。Copyright © 2022. Published by Elsevier B.V.

Somatic cell gene mutations arise in vivo due to replication errors during DNA synthesis occurring spontaneously during normal DNA synthesis or as a result of replication on a DNA template damaged by endogenous or exogenous mutagens. In principle, changes in the frequencies of mutant cells in vivo in humans reflect changes in exposures to exogenous or endogenous DNA damaging insults, other factors being equal. It is becoming increasingly evident however, that somatic mutations in humans have a far greater range of interpretations. For example, mutations in lymphocytes provide invaluable probes for in vivo cellular and molecular processes, providing identification of clonal amplifications of these cells in autoimmune and infectious diseases, transplantation recipients, paroxysmal nocturnal hemoglobinuria (PNH), and cancer. The assay for mutations of the X-chromosomal hypoxanthine guanine phosphoribosyltransferase (HPRT) gene has gained popular acceptance for this purpose since viable mutant cells can be recovered for molecular and other analyses. Although the major application of the HPRT T cell assay remains human population monitoring, the enrichment of activated T cells in the mutant fraction in individuals with ongoing immunological processes has demonstrated the utility of surrogate selection, a method that uses somatic mutation as a surrogate marker for the in vivo T cell proliferation that underlies immunological processes to investigate clinical disorders with immunological features. Studies encompassing a wide range of clinical conditions are reviewed. Despite the historical importance of the HPRT mutation system in validating surrogate selection, there are now additional mutational and other methods for identifying immunologically active T cells. These methods are reviewed and provide insights for strategies to extend surrogate selection in future studies.Copyright © 2022. Published by Elsevier B.V.