Expression of the T cell antigen receptor zeta chain following activation is controlled at distinct checkpoints - Implications for cell surface receptor down-modulation and re-expression

The multisubunit T cell antigen receptor (TCR) is involved in antigen recog nition and signal transduction, leading to T cell activation and rapid down -modulation of the cell surface expressed TCRs, Although the levels of TCR cell surface expression are pivotal to the efficiency and duration of the i mmune response, the molecular mechanisms controlling TCR down-modulation an d re-expression upon activation, remain obscure. Here, we provide a biochem ical characterization of the regulatory mechanisms governing TCR expression following long-term T cell activation. We focused primarily on the TCR zet a chain, as this is considered the limiting factor in TCR complex formation and transport to the cell surface. We found that following TCR-mediated ac tivation zeta mRNA is up-regulated by a transcription-dependent mechanism. Concomitantly, zeta protein levels are modified according to a biphasic pat tern: rapid degradation coinciding with TCR cell surface down-regulation, f ollowed by a rebound to normal levels 24 h subsequent to T cell activation. Even though there are adequate levels of all the TCR subunits within the c ell following 24 h of activation, TCR cell surface expression remained very low, provided the activating antibody is continuously present. Correlative with the latter, we detected a previously undescribed monomeric form of th e zeta chain. This form could be indicative of adverse endoplasmic reticulu m conditions affecting correct protein folding, dimerization, and TCR assem bly, all critical for optimal receptor surface re-expression. Cumulatively, our results indicate that the levels of TCR expression following activatio n, are tightly controlled at several checkpoints.