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 in the thyroid, recent studies have examined the molecular mechanisms regulating interferon-mediated induction of class I through the transcriptional co-activator CIITA and T cell specific class I expression. The CIITA co-activator is essential for transcriptional activation of MHC class II genes and mediates enhanced MHC class I transcription. 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 core promoter 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 TAF1 whereas CIITA activation does not. The distinct requirements of activated and constitutive transcription result in the selective usage of transcription start sites: activated transcription focuses transcription to downstream sites within the core promoter while constitutive transcription is primarily at upstream sites. Of particular interest is our recent finding that the MHC class I core promoter contains a series of downstream regulatory elements that contribute to regulating both constitutive and basal transcription. One of these elements is bifunctional: it represses constitutive, upstream start sites but enhances activated downstream start site usage. Thus, selective start site usage is regulated by a series of elements that allow extraordinary fine-tuning of transcription, to ensure that the correct level of class I is expressed to maintain immune surveillance without breaking tolerance. The importance of maintaining appropriate levels of MHC class I may also be relevant to tumor-cell based vaccine development. Tumor cells are generally poorly immunogenic, possibly because they have down-regulated MHC class I to levels below detection by adaptive immune surveillance but above those of innate immunity. Indeed, in recent studies, we have found that the Erk5 pathway, which is often constitutively expressed a variety of lymphoma cells, also regulates the transcription of MHC class I genes. These findings may provide new insights and approaches into the development of cell-based vaccines.
