Intercellular and intracellular events following the MHC-unrestricted TCR recognition of a tumor-specific peptide epitope on the epithelial antigen MUC1.
We examined the functional and molecular parameters involved in direct TCR recognition of a tumor-specific peptide epitope on the tumor Ag MUC1. This peptide epitope is tandemly repeated and recognized on the native molecule rather than processed and bound to the MHC. Even though the TCR was not MHC restricted, intercellular interactions found to facilitate this recognition included intercellular adhesion molecule-1/LFA-1, LFA-3/CD2, and class I/CD8. Intracellular parameters of MHC-unrestricted CTL activation were examined to compare the recognition of the MUC1 epitope presented on synthetic microspheres, with the recognition of the native epitope in the context of other molecules on the target cells. The epitope on microspheres induced a transient influx of Ca2+ that was not accompanied by detectable tyrosine phosphorylation of the zeta-associated protein ZAP-70, whereas recognition of MUC1 epitopes on tumor cells caused a sustained Ca2+ influx and ZAP-70 phosphorylation. The transient influx of Ca2+ was not sufficient to cause translocation of the nuclear factor of activated T cells (NF-AT) into the nucleus or CTL proliferation. In contrast, recognition of the MUC1 epitope on tumor cells resulted in full activation of the CTL, nuclear translocation of NF-AT, and proliferation. MHC-unrestricted TCR triggering, therefore, involves similar intercellular and intracellular events that participate in the conventional, MHC-restricted Ag recognition. Direct recognition of the MUC1 peptide epitope by the TCR in the absence of presentation by the MHC induces a partial signal that is completed by further interactions of other receptor/ligand pairs on the surface of the CTL and their target cells.
Magarian-Blander
J
J
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, PA 15261, USA.
Ciborowski
P
P
Hsia
S
S
Watkins
S C
SC
Finn
O J
OJ
D000595:Amino Acid Sequence; D001692:Biological Transport / Q000276:immunology; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism; D018968:CD58 Antigens / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D000939:Epitopes / Q000276:immunology*; D005110:Extracellular Space / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000276:immunology*; D008213:Lymphocyte Activation; D008863:Microspheres; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010455:Peptides / Q000276:immunology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
D018968:CD58 Antigens; D004268:DNA-Binding Proteins; D000939:Epitopes; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D018396:Mucin-1; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D018799:Intercellular Adhesion Molecule-1; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D002118:Calcium