Accolla R S, Scupoli M T, Cambiaggi C, Tosi G, Sartoris S
Istituto di Scienze Immunologiche, Facoltà di Medicina e Chirurgia, Università di Verona, Italy.
Int J Cancer Suppl. 1991;6:20-5. doi: 10.1002/ijc.2910470707.
In this report we present evidence and we review data from our laboratory which indicate the genetic complexity of regulatory mechanisms controlling MHC class-II-gene expression. The MHC class-II genes can be expressed in 2 ways: in a constitutive fashion, as in B cells, and in an inducible fashion, as in macrophages, endothelial cells and certain tumors. In both cases the regulatory controls are mainly exerted at transcriptional level as a result of interactions between cis-acting regulatory DNA elements and trans-acting factors. The constitutive class-II-gene expression in B cells is under the control of developmentally regulated trans-acting factors with activator function and encoded by a series of genes, the AIR genes, one of which has been mapped in the mouse on chromosome 16. Interestingly, these regulatory mechanisms are conserved across species for at least 70 million years, because murine AIR-gene products can complement AIR gene defects of human B-cell mutants. The constitutive B-cell phenotype behaves as a dominant trait up to the plasma cell stage in which class-II-gene expression is lost because of the activation of suppressor factors which repress transcription and which, in turn, behave as a dominant trait in somatic cell hybrids between B cells and plasma cells. Thus positive and negative signals regulating class-II-gene expression may behave as dominant or recessive traits, depending upon the particular developmental stage of the cell in which they operate. The mechanisms controlling class-II expression in inducible cells are distinct from those mediating constitutive expression. Indeed, induction of these genes is not sufficient to complement AIR-gene defects in hybrids between macrophages and class-II-negative mutant B cells. In contrast, constitutive expression is dominant in hybrids between class-II-positive B cells and macrophages, suggesting that in uninduced cells class-II-gene activation does not take place more because of lack of activator factors than because of the presence of constitutive transcriptional suppressors. On the basis of these results, we propose a model for developmentally controlled MHC class-II-gene expression during ontogeny.
在本报告中，我们展示了证据，并回顾了来自我们实验室的数据，这些数据表明控制MHC II类基因表达的调控机制具有遗传复杂性。MHC II类基因可以通过两种方式表达：以组成型方式表达，如在B细胞中；以诱导型方式表达，如在巨噬细胞、内皮细胞和某些肿瘤中。在这两种情况下，调控主要在转录水平上发挥作用，这是顺式作用调控DNA元件和反式作用因子之间相互作用的结果。B细胞中组成型II类基因的表达受具有激活功能的发育调控反式作用因子的控制，这些因子由一系列基因编码，即AIR基因，其中一个已在小鼠的16号染色体上定位。有趣的是，这些调控机制在至少7000万年的物种间是保守的，因为鼠类AIR基因产物可以补充人类B细胞突变体的AIR基因缺陷。组成型B细胞表型在浆细胞阶段之前表现为显性性状，在浆细胞阶段，由于抑制因子的激活，II类基因表达丧失，这些抑制因子抑制转录，而在B细胞和浆细胞之间的体细胞杂种中，这些抑制因子又表现为显性性状。因此，调节II类基因表达的正负信号可能表现为显性或隐性性状，这取决于它们发挥作用的细胞的特定发育阶段。控制诱导性细胞中II类表达的机制与介导组成型表达的机制不同。事实上，这些基因的诱导不足以补充巨噬细胞和II类阴性突变B细胞之间杂种中的AIR基因缺陷。相反，II类阳性B细胞和巨噬细胞之间的杂种中组成型表达是显性的，这表明在未诱导的细胞中，II类基因激活未发生更多是因为缺乏激活因子，而不是因为存在组成型转录抑制因子。基于这些结果，我们提出了一个在个体发育过程中发育控制的MHC II类基因表达模型。
