INTERCELLULAR AND INTRACELLULAR EVENTS FOLLOWING THE MHC-UNRESTRICTEDTCR RECOGNITION OF A TUMOR-SPECIFIC PEPTIDE EPITOPE ON THE EPITHELIALANTIGEN MUC1

We examined the functional and molecular parameters involved in direct TCR recognition of a tumor-specific peptide epitope on the tumor Ag M UC1. This peptide epitope is tandemly repeated and recognized on the n ative molecule rather than processed and bound to the MHC. Even though the TCR was not MHC restricted, intercellular interactions found to f acilitate this recognition included intercellular adhesion molecule-1/ LFA-1, LFA-3/CD2, and class I/CD8. Intracellular parameters of MHC-unr estricted CTL activation were examined to compare the recognition of t he MUC1 epitope presented on synthetic microspheres, with the recognit ion of the native epitope in the context of other molecules on the tar get cells. The epitope on microspheres induced a transient influx of C a2+ that was not accompanied by detectable tyrosine phosphorylation of the zeta-associated protein ZAP-70, whereas recognition of MUC1 epito pes on tumor cells caused a sustained Ca2+ influx and ZAP-70 phosphory lation. The transient influx of Ca2+ was not sufficient to cause trans location of the nuclear factor of activated T cells (NF-AT) into the n ucleus or CTL proliferation. In contrast, recognition of the MUC1 epit ope on tumor cells resulted in full activation of the CTL, nuclear tra nslocation of NF-AT, and proliferation. MHC-unrestricted TCR triggerin g, therefore, involves similar intercellular and intracellular events that participate in the conventional, MHC-restricted Ag recognition. D irect recognition of the MUC1 peptide epitope by the TCR in the absenc e of presentation by the MHC induces a partial signal that is complete d by further interactions of other receptor/ligand pairs on the surfac e of the CTL and their target cells.