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Abstract
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.
Highlights
Immunotherapy based on active immunization is an increasingly applied adjuvant therapy for the treatment of hemopoietic and epithelial tumors
We show by double staining of thymic sections with anti-EpCAM and anti-MUC1 monoclonal antibodies (mAbs) that MUC1 expression in the thymic medulla was confined to rare medullary thymic epithelial cells (mTECs), whereas there was no detectable expression in the cortex (Fig. 1A)
Both MUC1- and carcinoembryonic antigen (CEA)-positive cells tended to cluster in the vicinity and the outer rim of Hassal’s corpuscles (HC), a site where terminally differentiated mTECs cluster [22]
Summary
Immunotherapy based on active immunization is an increasingly applied adjuvant therapy for the treatment of hemopoietic and epithelial tumors. Antigens, which are induced or highly up-regulated in tumor cells, are classified as self-antigens These self-antigens can potentially still be seen as foreign when posttranslational mechanisms like glycosylation have been altered due to oncogenic transformation. With the assumption that antigens with a spatially and/or temporally restricted expression pattern (i.e., oncofetal or cancer germ cell antigens) may be exempt from tolerance induction, such antigens have been preferentially selected for clinical trials [5]. This assumption has been questioned recently with the demonstration that members of these types of TAA are expressed in medullary thymic epithelial cells (mTECs), along with a host of other tissue-restricted self-antigens, a phenomenon termed ‘‘promiscuous gene expression’’ [6, 7]. Differences in posttranslational modifications between thymic and peripheral (tissue or tumor-restricted) antigen expression could conceivably result in incomplete self-tolerance [10, 11]
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