Qualitative and quantitative contributions of the T cell receptor ζ chain to mature T cell apoptosis

Abstract

Engagement of the T cell receptor (TCR) of mature T lymphocytes can lead either to activation/proliferation responses or programmed cell death. To understand the molecular regulation of these two fundamentally different outcomes of TCR signaling, we investigated the participation of various components of the TCR-CD3 complex. We found that the TCR-ζ chain, while not absolutely required, was especially effective at promoting mature T cell apoptosis compared with the CD3ε, γ, or δ chains. We also carried out mutagenesis to address the role of the immunoreceptor tyrosine-based activation motifs (ITAMs) that are the principal signaling components found three times in the TCR-ζ chain and trace in each of the CD3ε, γ, or δ chains. We found that the ability of the TCR-ζ chain to promote apoptosis results both from a quantitative effect of the presence of multiple ITAMs as well as qualitatively different contributions made by individual ITAMs. Apoptosis induced by single chain chimeras revealed that the first ζ ITAM stimulated greater apoptosis than the third ζ ITAM, and the second ζ. ITAM was unable to trigger apoptosis. Because microheterogeneity in the amino acid sequence of the various ITAM motifs found in the TCR-ζ and CD3 chains predicts interactions with distract src homology-2-domain signaling proteins, our results suggest the possibility that individual ITAM motifs might play unique roles in TCR, responses by engaging specific signaling pathways.