The T-cell antigen receptor: a complex signal-transducing molecule.
The T cell antigen-specific receptor (TCR) on most mature T cells is a multisubunit complex composed of 7 chains: alpha, beta, gamma, delta, epsilon, and either a zeta-zeta homodimer (zeta 2) or a zeta-eta heterodimer (zeta eta). We have derived a series of TCR variants and mutants from the antigen-specific murine T cell hybridoma, 2B4.11, permitting detailed analyses of the assembly and transport of the TCR. Loss of the zeta chain resulted in markedly reduced cell surface TCR expression. This was due to enhanced degradation of the other TCR chains in a post-Golgi, probably lysosomal, compartment. Loss of the beta chain, delta chain, or the combination of delta and zeta chains, also resulted in loss of cell surface TCR expression. Unlike the zeta loss variants, in these cases the other TCR chains were retained in the ER. Epsilon, gamma, and zeta could survive for prolonged periods in the ER, while the alpha, beta, and delta chains were rapidly and efficiently degraded. In another series of studies, variants that were deficient in the eta chain but that expressed normal levels of zeta 2-containing TCRs were analyzed for their functional properties. A positive relationship was found between the presence of zeta eta and the ability to respond to mitogenic stimuli with increases in phosphoinositide hydrolysis and, in one well characterized variant, increases in intracellular Ca2+. Despite this, late biological responses such as interleukin 2 (IL-2) production and inhibition of transformed growth were relatively normal. These results call into question the putative cause-and-effect relationship between some early biochemical events and these late biological responses. Further, they suggest a model in which zeta eta-containing TCR complexes are largely responsible for activation-induced phosphoinositide hydrolysis.
Bonifacino
J S
JS
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bethesda, Maryland 20892.
Merćep
M
M
Sussman
J J
JJ
Klausner
R D
RD
Ashwell
J D
JD
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology; D017252:CD3 Complex; D002118:Calcium / Q000378:metabolism; D005786:Gene Expression Regulation; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D007295:Inositol Phosphates; D011948:Receptors, Antigen, T-Cell; D002118:Calcium