Boehm T, Rabbitts T H
Medical Research Council Laboratory of Molecular Biology, Cambridge, England.
FASEB J. 1989 Oct;3(12):2344-59. doi: 10.1096/fasebj.3.12.2676678.
T cells express either of the two forms of antigen-specific receptors, the alpha/beta and gamma/delta heterodimers. Their structure closely resembles that of immunoglobulins, and the variable part of the receptor molecule is created by somatic assembly of variable, diversity, and joining regions. The genetic structure of T cell receptor (TCR) genes and their rearrangement in T cell development have been elucidated in great detail in recent years. The human genes for the gamma and beta subunits are located on the short and long arms of chromosome 7, respectively, whereas the delta- and alpha-chain genes are located in tandem on the centromeric half of the long arm of chromosome 14. Expression of either alpha/beta or gamma/delta TCR complexes on T cells in the developing thymus is likely to proceed in an ordered fashion and results in the appearance of distinct T cell subpopulations. The process of DNA rearrangements required for the generation of functional variable region genes also predisposes lymphoid cells to aberrant DNA rearrangements, which can be detected as chromosomal abnormalities such as translocations and inversions. Molecular analysis of such aberrant rearrangements has shown that rearranging loci are fused to loci unrelated to antigen receptor genes. Furthermore, the breakpoint structures represent nonproductive intermediates in the hierarchy of physiological rearrangements. Accordingly, T cell tumors arising early in T cell development often carry chromosomal abnormalities involving the delta-chain locus, whereas tumors generated later in T cell development tend to show aberrations in the alpha-chain gene. This pattern seems to reflect the stage-specific accessibility of TCR loci for rearrangement by the recombinase machinery. This enzyme is guided by specific recombination signals that can sometimes also be found at the site of breakage on the participating locus in chromosomal abnormalities. Although some features of the mechanism of aberrant rearrangements are known, their biological consequences are less well understood. However, molecular analysis of the mechanism of chromosomal aberrations in T cell tumors suggests that their biological consequences may vary. Firm evidence for the pathogenic significance is missing for most of these lesions. This provides a challenge to molecular immunology to determine how chromosomal abnormalities are involved in tumor pathogenesis.
T细胞表达两种形式的抗原特异性受体，即α/β和γ/δ异二聚体。它们的结构与免疫球蛋白的结构非常相似，受体分子的可变部分是由可变区、多样区和连接区的体细胞组装产生的。近年来，T细胞受体（TCR）基因的遗传结构及其在T细胞发育过程中的重排已得到详细阐明。γ和β亚基的人类基因分别位于7号染色体的短臂和长臂上，而δ链和α链基因则串联位于14号染色体长臂着丝粒的一半上。发育中的胸腺中T细胞上α/β或γ/δTCR复合物的表达可能以有序的方式进行，并导致不同T细胞亚群的出现。产生功能性可变区基因所需的DNA重排过程也使淋巴细胞易发生异常DNA重排，这可被检测为染色体异常，如易位和倒位。对这种异常重排的分子分析表明，重排位点与抗原受体基因无关的位点融合。此外，断点结构代表生理重排层次中的非生产性中间体。因此，在T细胞发育早期出现得T细胞肿瘤通常携带涉及δ链位点的染色体异常 , 而在T细胞发育后期产生的肿瘤往往显示α链基因的畸变。这种模式似乎反映了TCR位点对重组酶机制重排的阶段特异性可及性。这种酶由特定的重组信号引导，这些信号有时也可以在染色体异常中参与位点的断裂部位找到。虽然异常重排机制的一些特征是已知的，但其生物学后果了解较少。然而，对T细胞肿瘤中染色体畸变机制得分子分析表明，其生物学后果可能各不相同。这些病变中大多数缺乏致病意义的确凿证据。这给分子免疫学带来了挑战，以确定染色体异常如何参与肿瘤发病机制。
