Developmental regulation of αβ T cell antigen receptor expression results from differential stability of nascent TCRα proteins within the endoplasmic reticulum of immature and mature T cells

The αβ T cell antigen receptor (TCR) that is expressed on most T lymphocytes is a multisubunit transmembrane complex composed of at least six different proteins (α, β, γ, δ, ε and ζ that are assembled in the endoplasmic reticulum (ER) and then transported to the plasma membrane. Expression of the TCR complex is quantitatively regulated during T cell development, with immature CD4⁺ CD8⁺ thymocytes expressing only 10% of the number of surface αβ TCR complexes that are expressed on mature T cells. However, the molecular basis for low TCR expression in developing αβ T cells is unknown. In the present study we report the unexpected finding that assembly of nascent component chains into complete TCRαβ complexes is severely impaired in immature CD4⁺ CD8⁺ thymocytes relative to their mature T cell progeny. In particular, the initial association of TCRα with TCRβ proteins, which occurs relatively efficiently in mature T cells, is markedly inefficient in immature CD4⁺CD8⁺ thymocytes, even for a matched pair of transgenic TCRα and TCRβ proteins. Inefficient formation of TCRαβ heterodimers in immature CD4⁺CD8⁺ thymocytes was found to result from the unique instability of nascent TCRα proteins within the ER of immature CD4⁺ CD8⁺ thymocytes, with nascent TCRα proteins having a median survival time of only 15 min in CD4⁺CD8⁺ thymocytes, but >75 min in mature T cells. Thus, these data demonstrate that stability of TCRα proteins within the ER is developmentally regulated and provide a molecular basis for quantitative differences in αβ TCR expression on immature and mature T cells. In addition, these results provide the first example of a receptor complex whose expression is quantitatively regulated during development by post-translational limitations on receptor assembly.