Responses of MHC Class I Genes to Exogeneous Stimuli

MHC I类表达受组织特异性和激素调节机制的影响。MHC I类的表达受到多种刺激的动态调节。诸如TNF和干扰素之类的药物是众所周知的I类转录诱导剂。相反，促甲状腺激素（TSH）特异性地降低甲状腺细胞中I类基因的转录；这种下调是camp介导的。先前的实验室研究主要集中在tsh介导的抑制机制上，而最近的研究正在通过转录共激活剂CIITA研究干扰素介导的诱导的分子基础。CIITA共激活因子对MHC II类基因的转录激活至关重要，并介导MHC I类转录的增强。CIITA激活I类启动子需要下游核心启动子和上游序列。激活完全依赖于上游的CRE，位于-100和-107 bp之间，但进一步增强了一系列上游序列元素。有趣的是，CIITA介导的激活所需的DNA序列不同于构成型转录。此外，CIITA激活所需的转录因子也不同于构成型转录：构成型转录需要TAFII250，而CIITA激活则不需要。在不同组织中表达水平也有很大差异，在淋巴细胞室、T细胞和B细胞中，I类表达水平最高。虽然已知B细胞中的高I类表达涉及含有ciita的B细胞增强体，但尚未探索T细胞中高组成型I类表达的分子基础。T细胞特异性基因，如T细胞受体基因，由T细胞增强体RUNX1、CBF？r， LEF1和Aly。在本报告中，我们证明了MHC I类基因的表达被T细胞增强体增强，并且是体内含有runx1的复合物与I类基因直接相互作用的结果。T细胞增强体激活I类转录与干扰素-?？(干扰素吗? ?w介导的激活和靶向反应元件与IFN靶向的元件不同？这些发现为T细胞中高水平的MHC I类提供了分子基础。

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?r, 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???w mediated activation and targets response elements distinct from those targeted by IFN???|?n?nThese findings provide a molecular basis for the high levels of MHC class I in T cells.