title: MUC1 is a novel costimulatory molecule of human T cells and functions in an AP-1-dependent manner.
abstract: MUC1 mucin, primarily known as an epithelial antigen, has been demonstrated to be expressed on activated human T cells. In the present study, we first examined the expression of MUC1 on different subsets of T cells (naive, effector, effector/memory). MUC1 appears to be strongly upregulated on activated CD4(+) T cells in comparison with CD8(+) T cells. The cytoplasmic tail of MUC1 contains both immune tyrosine-based activation and inhibitory motifs; therefore, we investigated whether MUC1 can also act as a costimulatory molecule on human T cells. Nonpurified T-cell cultures from human peripheral blood exhibited enhanced proliferation and an increase in cytokine production when CD3 and MUC1 were cross-linked and coligated. The intracellular mechanism of MUC1-mediated costimulation was determined to be mediated by the calcium-dependent NF-AT pathway. We further demonstrated that the cytoplasmic tail of MUC1 binds to the AP-1 transcription factors c-Fos and c-Jun, with c-Fos binding constitutively and c-Jun binding only after MUC1 stimulation. Their nuclear migration is then facilitated in a CD3-dependent manner. Our findings clearly demonstrate that MUC1 is a novel T-cell costimulatory molecule involved in immune regulation. These studies delineate important mechanisms of T-cell activation and regulation.
authors.affiliation: Department of Surgery, Faculty of Medicine, Dentistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Konowalchuk
authors.forename: Babita
authors.initials: B
authors.lastname: Agrawal
mesh_terms: D000328:Adult; D000906:Antibodies / Q000737:chemistry / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000737:chemistry; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016762:Genes, fos / Q000235:genetics / Q000276:immunology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008875:Middle Aged; D018396:Mucin-1 / Q000235:genetics / Q000276:immunology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000276:immunology*
chemical_list: D000906:Antibodies; D017252:CD3 Complex; D003432:Cross-Linking Reagents; C060192:MUC1 protein, human; D018396:Mucin-1; D010835:Phytohemagglutinins; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases