T cell receptor ζ allows stable expression of receptors containing the CD3γ leucine-based receptor-sorting motif

The leucine-based motif in the T cell receptor (TCR) subunit CD3 gamma constitutes a strong internalization signal. In fully assembled TCR this motif is inactive unless phosphorylated, In contrast, the motif is constitutively active in CD4/CD3 gamma and Tac/CD3 gamma chimeras independently of phosphorylation and leads to rapid internalization and sorting of these chimeras to lysosomal degradation. Because the TCR zeta chain rescues incomplete TCR complexes from lysosomal degradation and allows stable surface expression of fully assembled TCR, we addressed the question whether TCR zeta has the potential to mask the CD3 gamma leucine-based motif. By studying CD4/CD3 gamma and CD16/CD3 gamma chimeras, we found that CD16/CD3 gamma chimeras associated with TCR zeta. The CD16/CD3 gamma-TCR zeta complexes were stably expressed at the cell surface and had a low spontaneous internalization rate, indicating that the leucine-based motif in these complexes was inactive. In contrast, the CD4/CD3 gamma chimeras did not associate with TCR zeta, and the leucine-based motif in these chimeras was constitutively active resulting in a high spontaneous internalization rate and low expression of the chimeras at the cell surface. Thus, our data demonstrate that TCR zeta allows stable cell surface expression of receptors containing CD3 gamma leucine-based motifs by its potential to mask such motifs.