Responses of MHC Class I Genes to Exogeneous Stimuli

MHC-I类分子的表达受组织特异性和激素调节机制的影响。MHC-I类分子的表达受多种刺激的动态调节。众所周知，肿瘤坏死因子和干扰素是I类转录的诱导剂。相反，促甲状腺激素(TSH)特异性地减少甲状腺细胞中I类基因的转录；这种下调是由cAMP介导的。实验室以前的研究主要集中在TSH介导的抑制机制上，而最近的研究正在研究干扰素通过转录共激活因子CIITA介导的诱导的分子基础。CIITA共激活子对于MHC-II类基因的转录激活是必不可少的，并介导增强的MHC-I类转录。CIITA对I类启动子的激活既需要下游核心启动子，也需要上游序列。激活完全依赖于上游的Cre，位于-100到-107bp之间，但一系列上游序列元件进一步增强了激活。有趣的是，CIITA介导的激活对DNA序列的要求与构成转录的不同。此外，CIITA激活对转录因子的要求也不同于构成性转录：构成性转录需要TAFII250，而CIITA激活不需要。不同组织的表达水平也有很大差异，I类基因的最高水平出现在淋巴室、T细胞和B细胞中。虽然已知B细胞中高表达的ClassI与含有CIITA的B细胞增强体有关，但T细胞中高结构型ClassI表达的分子基础尚未被探索。T细胞特异性基因，如T细胞受体基因，受由RUNX1、CBF、LEF1和Aly组成的T细胞增强体的调控。在这篇报道中，我们证明了MHC I类基因的表达是由T细胞增强体增强的，并且是含有RUNX1的复合体与I类基因在体内直接相互作用的结果。T细胞I类转录的增强小体激活与干扰素介导的激活和靶向反应元件具有协同作用，这些发现为T细胞中高水平的MHC I类转录提供了分子基础。

MHC class I expression is subject to both tissue-specific and hormonal regulatory mechanisms. Expression of MHC class I is dynamically regulated in response to a variety of stimuli. Agents such as TNF and interferon are well known inducers of class I transcription. In contrast, thyroid stimulating hormone (TSH) specifically reduces class I gene transcription in thyrocytes; this down-regulation is cAMP-mediated. Whereas previous studies in the laboratory have focused on the mechanisms of TSH-mediated repression, recent studies are examining the molecular basis of interferon-mediated induction through the transcriptional co-activator CIITA. The CIITA co-activator is essential for transcriptional activation of MHC class II genes and mediates enhanced MHC class I transcription. Class I promoter activation by CIITA requires both the downstream core promoter and upstream sequences. Activation is absolutely dependent on the upstream CRE, located between -100 and -107 bp, but is further enhanced by a series of upstream sequence elements. Interestingly, the DNA sequence requirements for CIITA mediated activation are distinct from those of constitutive transcription. Furthermore, the transcription factor requirements for CIITA activation are also distinct from those of constitutive transcription: constitutive transcription requires TAFII250 whereas CIITA activation does not.Levels of expression also vary widely among tissues, with the highest levels of class I occurring in the lymphoid compartment, in T cells and B cells. While the high class I expression in B cells is known to involve the CIITA-containing B cell enhanceosome, the molecular basis for high constitutive class I expression in T cells has not been explored. T cell specific genes, such as T cell receptor genes, are regulated by a T cell enhanceosome consisting of RUNX1, CBF, LEF1 and Aly. In this report, we demonstrate that MHC class I gene expression is enhanced by the T cell enhanceosome and results from a direct interaction of the RUNX1-containing complex with the class I gene in vivo. T cell enhanceosome activation of class I transcription is synergistic with interferon- (IFN mediated activation and targets response elements distinct from those targeted by IFN These findings provide a molecular basis for the high levels of MHC class I in T cells.