| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1994: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1993: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Research Abstract |
The alphabeta T cell antigen receptor (TCR) that is expressed on most T lymphocytes is a multisubunit transmembrane complex composed of at least six different proteins (alpha, beta, gamma, delta, epsilon and zeta) 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 surfce alphabeta TCR complexes that are expressed on mature T cells. However, the molecular basis for low TCR expression in developing alphabeta T cells is unknown. In the present study we report the the unexpected finding that assembly of nascent component chains into complete TCRalphabeta complexes is severely impaired in immature CD4^+CD8^+ thymocytes relative to their mature T cell progeny. In particular, the initial association of TCR alpha with TCR beta proteins, which occurs relatively efficiently in mature T cells, is markedly inefficient in immature CD4^+CD8^+ thymocytes, even for a matched pair of transgenic TCR alpha and TCR beta proteins. Inefficient formation of TCRalphabeta heterodimers in immature CD4^+CD8^+ thymocytes was found to result from the unique instability of nascent TCR alpha proteins within the ER of immature CD4^+CD8^+ thymocytes, with nascent TCR alpha 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 TCR alpha proteins within the ER is developmenally regulated and provide a molecular basis for quantitative differences in alphabeta 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 posttranslational limitations on receptor assembly.
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