Novel post-translational regulation of TCR expression in CD4+CD8+ thymocytes influenced by CD4.
Expression of the multicomponent T-cell antigen receptor (TCR) complex on the surface of thymocytes is developmentally controlled. Most immature CD4-CD8- 'double negative' and CD4+CD8+ 'double positive' thymocytes express either no or few TCR on their surface, and maturation to CD4+CD8- or CD4-CD8+ 'single positive' thymocytes is accompanied by a dramatic increase in the number of surface TCR complexes. Although the initial appearance of TCR during differentiation results from rearrangement and initiation of transcription of TCR genes in the thymus, the mechanisms regulating the quantitative changes in TCR expression during intrathymic differentiation are unknown. Surface TCR levels in T-hybridoma cells can be quantitatively regulated by a series of post-translational processes, including sorting to alternative intracellular compartments and degradation, which ensure that only fully and correctly assembled receptor complexes are efficiently transported to the cell surface. Quantitative increases in TCR expression on the surface of CD4+CD8+ thymocytes occur in vivo in response to anti-CD4 antibody treatment. Here we present evidence that immature CD4+CD8+ thymocytes normally retain and degrade in the endoplasmic reticulum greater than 90% of some endogenously synthesized TCR chains, and that the increased surface TCR expression on immature CD4+CD8+ thymocytes induced by anti-CD4 is due to an increase in the escape of newly synthesized receptor chains from the endoplasmic reticulum, and is not due to increases in RNA levels, translation, or assembly. Post-translational mechanisms therefore control the levels of TCR complexes on CD4+CD8+ thymocytes, and these mechanisms can be modulated by signalling through CD4 surface molecules.
Bonifacino
J S
JS
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
McCarthy
S A
SA
Maguire
J E
JE
Nakayama
T
T
Singer
D S
DS
Klausner
R D
RD
Singer
A
A
D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D015151:Immunoblotting; D007163:Immunosorbent Techniques; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D011499:Protein Processing, Post-Translational; D012313:RNA / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D015854:Up-Regulation
D015703:Antigens, CD; D015704:CD4 Antigens; D011948:Receptors, Antigen, T-Cell; D012313:RNA