Developmentally controlled and tissue-specific expression of unrearranged VH gene segments

It is generally accepted that unrearranged immunoglobulin VH gene segments are not expressed and that assembly of a complete heavy chain gene is required to activate a previously silent VH promoter. We report that unrearranged VH gene segments are indeed expressed at a high level, but only in a developmentally controlled and tissue-specific manner. Unrearranged VH expression is limited to the very early stages of the B-lymphocyte differentiation pathway, and it is most prominent in cells undergoing VH to DJH rearrangement. Germ-line VH expression is independent of the heavy chain enhancer, may be controlled by 5' sequence elements, and is repressible by LPS. In contrast to earlier interpretations, our results demonstrate that the lack of unrearranged VH segment expression in mature, Ig-secreting cells is due to the inactivation of a previously active locus. These findings may provide insight into the mechanisms that control ordered rearrangement and allelic exclusion.