Pleiotropic loss of activation pathways in a T-cell receptor α-chain deletion variant of a cytolytic T-cell clone

Abstract

Untransformed T-cell clones maintained in culture are dependent on signals transmitted through their antigen receptors (Ti; α and β chains associated with the CD3 molecules) for growth and effector function^1,2. For cytolytic T cells (CTL), Ti stimulation also activates the killing machinery³ and induces synthesis of gamma interferon (IFN-γ) messenger RNA and IFN-γ secretion⁴. The Thy-1 molecule, expressed on all murine cells of the T-cell lineage, has been suggested to function in transmembrane signalling, based on the ability of some anti-Thy-1 monoclonal antibodies (mAb) to activate T cells^5–9. Recently, it was suggested that Thy-1 could function as a signal-transduction molecule when expressed in B-cell lymphomas after transfection of the gene, leading to speculation that the molecule was part of an activation pathway independent of the Ti/CD3 structures¹⁰. Here we report the immunoselection of a variant CTL clone which has lost expression of mRNA for the α-chain of the Ti. The Ti^- variant was defective in lectin-mediated activation whether measured by increase in intracytoplasmic Ca²⁺, CTL effector function or IFN-y synthesis. The variant, which expressed normal levels of Thy-1, was also unresponsive to Thy-1 mAb activation as measured by IFN-γ secretion, whereas it responded to calcium ionophore plus phorbol ester. These results indicate that in a non-transformed, functional mature T-cell, Thy-1 mediated signalling is not an alternative to, but might depend on elements associated with the Ti/CD3-mediated T-cell activation pathway.