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Intercellular and Intracellular Events Following the MHC-Unrestricted TCR Recognition of a Tumor-Specific Peptide Epitope on the Epithelial Antigen MUC1¹

Julie Magarian-Blander^2,*, Pawel Ciborowski^*, Shyuan Hsia, Simon C. Watkins and Olivera J. Finn^3,*

Departments of ^* Molecular Genetics and Biochemistry, and Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; and Department of Pathology, Allegheny General Hospital, Pittsburgh, PA 15212

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 -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.

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