An Endoplasmic Reticulum Retention Function for the Cytoplasmic Tail of the Human Pre–T Cell Receptor (Tcr) α Chain

The pre-T cell receptor (TCR), which consists of a TCR-β chain paired with pre–TCR-α (pTα) and associated with CD3/ζ components, is a critical regulator of T cell development. For unknown reasons, extremely low pre-TCR levels reach the plasma membrane of pre-T cells. By transfecting chimeric TCR-α–pTα proteins into pre-T and mature T cell lines, we show here that the low surface expression of the human pre-TCR is pTα chain dependent. Particularly, the cytoplasmic domain of pTα is sufficient to reduce surface expression of a conventional TCR-α/β to pre-TCR expression levels. Such reduced expression cannot be attributed to qualitative differences in the biochemical composition of the CD3/ζ modules associated with pre-TCR and TCR surface complexes. Rather, evidence is provided that the pTα cytoplasmic tail also causes a reduced surface expression of individual membrane molecules such as CD25 and CD4, which are shown to be retained in the endoplasmic reticulum (ER). Native pTα is also observed to be predominantly ER localized. Finally, sequential truncations along the pTα cytoplasmic domain revealed that removal of the COOH-terminal 48 residues is sufficient to release a CD4-pTα chimer