Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells.

Thymic epithelial cells (TEC) form the structural and functional microenvironment necessary for the establishment and quality control of the T cell repertoire. In addition, they provide an ectopic source of numerous tissue-restricted antigens (TRA), a feature called promiscuous gene expression (pGE). How the regulation of pGE is related to the cell biology of TEC subset(s), e.g. their turnover and developmental interrelationship is still poorly understood. The observation that pGE is foremost a property of phenotypically and functionally mature medullary TEC (mTEC) implies that the full implementation of pGE is contingent on mTEC differentiation. Here, we show that the emergence of TEC subsets and pGE is tightly correlated during ontogeny and we provide evidence that mature CD80pos mTEC develop from an immature CD80neg subset. This differentiation step proceeds continuously in the postnatal thymus. While mature mTEC turnover in 2 to 3 weeks, immature mTEC encompass a smaller cycling and a larger non-cycling pool. The latter might serve as a reservoir of committed precursors, which sustain this renewal process. Our data document that mTEC represent a highly dynamic cell population, and they imply that the availability and display of TRA in the thymus undergoes a perpetual temporal and spatial reorganization.

Expression of tumor-associated differentiation antigens, MUC1 glycoforms and CEA, in human thymic epithelial cells: implications for self-tolerance and tumor therapy.

Expression of tissue-restricted self-antigens in the thymus, termed promiscuous gene expression, imposes T cell tolerance and protects from autoimmune diseases. This antigen pool also includes various types of tumor-associated antigens (TAA) previously thought to be secluded from the immune system. The scope of promiscuous gene expression has been defined by mRNA analysis at the global level of isolated medullary thymic epithelial cells (mTECs). Information at the protein level on the frequency of mTECs expressing a given antigen, on coexpression patterns, and post-translational modifications is largely missing. We report here promiscuous expression at the protein level of two TAA, MUC1 and CEA, in situ and in purified human mTECs. Both antigens are expressed in 1% to 3% of mTECs, either individually or coexpressed in the same cell. Using a panel of anti-MUC1 monoclonal antibodies recognizing different post-translational modifications, i.e., glycoforms of MUC1, we show that only fully glycosylated forms of MUC1 and the differentiation-dependent glycoforms were detected on mTECs, but not the cancer-associated glycoforms. Our findings imply that MUC1 and CEA are amenable to central tolerance induction, which might, however, be incomplete in case of tumor cell-restricted MUC1 glycoforms. Knowledge of these subtleties in promiscuous gene expression may, in the future, assist the selection of T cell tumor vaccines for clinical trials.