An orderly inactivation of intracellular retention signals controls surface expression of the T cell antigen receptor

Exit from the endoplasmic reticulum (ER) is an important checkpoint for proper assembly of multimeric plasma membrane receptors. The six subunits of the T cell receptor (TCR; TCRα, TCRβ, CD3γ, CD3δ, CD3ɛ, and CD3ζ) are each endowed with ER retention/retrieval signals, and regulation of its targeting to the plasma membrane is therefore especially intriguing. We have studied the importance of the distinct ER retention signals at different stages of TCR intracellular assembly. To this end, we have characterized first the presence of ER retention signals in CD3γ. Despite the presence of multiple ER retention signals in CD3γ, ɛγ dimers reach the cell surface when the single CD3ɛ ER retention signal is deleted. Furthermore, inclusion of this CD3ɛ mutant promoted plasma membrane expression of incomplete αβγɛ and αβδɛ complexes without CD3ζ. It therefore appears that the CD3ɛ ER retention signal is dominant and that it is only overridden upon the incorporation of CD3ζ. We propose that the stepwise assembly of the TCR complex guarantees that all assembly intermediates have at least one functional ER retention signal and that only a full signaling-competent TCR complex is expressed on the cell surface.