The regulation of HLA class I expression: is HLA-G the odd one out?

The expression of HLA-G in extravillous cytotrophoblast cells coincides with a general lack of classical MHC class I expression in this tissue. This differential expression of HLA-G and classical HLA class I molecules in trophoblasts suggests a tight transcriptional control. Transactivation of classical MHC class I genes is mediated by two groups of juxtaposed cis -acting elements which can be viewed as regulatory modules. The most up-stream module consists of the enhancer A and ISRE, and mediates the constitutive and cytokine-induced expression. The recently identified S-X-Y module is important in the constitutive and CIITA mediated transactivation. Both modules are divergent in HLA-G rendering this gene unresponsive to NF-kappaB, IRF-1, and CIITA mediated induction pathways. However, other known regulatory sequences that could contribute to the tissue-specific expression of HLA-G have so far not been identified in the proximal promoter region (-1500 bp) and in the first five intronic sequences. This implies a unique regulation of HLA-G transcription. Here, the transcriptional control of HLA-G and classical class I molecules in trophoblast cells are discussed.