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.
Cloosen
Silvie
S
Division of Hematology, Department of Internal Medicine, Growth and Development Research Institute, University Hospital Maastricht, the Netherlands.
Arnold
Janna
J
Thio
Marco
M
Bos
Gerard M J
GM
Kyewski
Bruno
B
Germeraad
Wilfred T V
WT
D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D002675:Child, Preschool; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018396:Mucin-1; D009077:Mucins / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D020033:Protein Isoforms; D017634:Self Tolerance / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; C060192:MUC1 protein, human; D018396:Mucin-1; D009077:Mucins; D020033:Protein Isoforms