The TCR/CD3 complex is composed of six subunits which are expressed on the cell surface in a coordinate fashion after assembly in the endoplasmic reticulum (ER). The TCR/CD3 complex is assembled after a series of pairwise interactions involving the formation of dimers of CD3 epsilon with either CD3 gamma or CD3 delta. These dimers assemble with TCR alpha and TCR beta chains, and finally, the CD3 zeta homodimer is added to allow export of the full complex from the ER. A model has been proposed suggesting that during assembly the CD3 epsilon/CD3 gamma dimer interacts exclusively with TCR beta and the CD3 epsilon/CD3 delta dimer with TCR alpha to form a complex with a single TCR alpha/beta heterodimer. We show in this study, by immunoprecipitation and two-dimensional gel electrophoresis, that in the human T cell line Jurkat as well as in total human thymocytes, this preferential interaction does not occur and instead, the CD3 epsilon/CD3 gamma and CD3 epsilon/CD3 delta dimers associate with both TCR chains simultaneously and indistinctly. These data are confirmed by the analysis of the TCR alpha-negative T cell line MOLT-4 in which TCR beta is found separately associated with CD3 epsilon/CD3 gamma and with CD3 epsilon/CD3 delta dimers. Indirectly, our results support a model of stoichiometry in which two TCR alpha/beta heterodimers are present in a TCR/CD3 complex. Furthermore, immunoprecipitation with anti-CD3 gamma and anti-CD3 delta antibodies from 1% NP40 and 1% Brij96 cell lysates showed that these subunits form independent partial complexes which are cross-linked through the CD3 zeta homodimer. This suggests that CD3 zeta mediates the interaction between both TCR alpha/beta heterodimers contained in the double TCR complex. Further proof for this hypothesis is obtained after analysis of a Jurkat cell transfectant containing a point mutation in the transmembrane domain of TCR beta that impairs the association of CD3 zeta. In this mutant cell line, unlike a control line with wild-type TCR beta, the CD3 gamma- and CD3 delta-containing complexes were found completely independent. Altogether, these results support a model of TCR/CD3 assembly and stoichiometry in which two TCR-alpha/beta heterodimers form two hemicomplexes containing either CD3 epsilon/gamma or CD3 epsilon/delta dimers which become associated via the CD3 zeta homodimer.
Interacting selectively and non-covalently with a protein kinase, any enzyme that catalyzes the transfer of a phosphate group, usually from ATP, to a protein substrate.
How membrane receptors initiate signal transduction upon ligand binding is a matter of intense scrutiny. The T cell receptor complex (TCR-CD3) is composed of TCR alpha/beta ligand binding subunits bound to the CD3 subunits responsible for signal transduction. Although it has long been speculated that TCR-CD3 may undergo a conformational change, confirmation is still lacking. We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3 epsilon and results in recruitment of the adaptor protein Nck. This occurs earlier than and independently of tyrosine kinase activation. Finally, by interfering with Nck-CD3 epsilon association in vivo, we demonstrate that TCR-CD3 recruitment of Nck is critical for maturation of the immune synapse and for T cell activation.
CD3 gamma, delta, epsilon, and zeta proteins together with the pre-TCR alpha-chain (pT alpha) and a rearranged TCR beta-chain assemble to form the pre-TCR that controls the double negative (DN) to double positive (DP) stages of thymopoiesis. The CD3 proteins are expressed before pT alpha and TCR beta-chains in prothymocytes and are expressed intracellularly in precursor NK cells, suggesting that the CD3 complex may function independent of pT alpha and TCR beta. In this report, both the role of CD3 epsilon exclusively, and the role of CD3 proteins collectively, in thymocyte and NK cell development were examined. In a mouse strain termed E delta P, a neomycin cassette inserted within the CD3 epsilon promoter abolishes CD3 epsilon and delta expression and also abolishes CD3 gamma expression in all but a small minority (< or =1%) of prothymocytes. These prothymocytes became deficient in CD3 epsilon alone upon reconstitution of CD3 delta expression and were severely, but not completely, arrested at the DN stage, as small numbers of double positive thymocytes were detected. In de facto CD3 gamma delta epsilon zeta(null) mice generated by crossing the epsilon delta P mice with CD3 zeta-/- mice, thymopoiesis were arrested at the CD44-CD25+ DN stage as observed in RAG-/- mice, DJ and VDJ recombination at the TCR beta locus was functional, and normal numbers of NK cells were detected. Together, the findings demonstrate that during thymocyte development, the CD3 complex collectively is not essential until the critical CD44-CD25+ DN stage in which pre-TCR begins to function, whereas CD3 epsilon is critical for the assembly of pre-TCR. Moreover, CD3 proteins are dispensable for NK cell development.
Conveys a signal from an upstream receptor or intracellular signal transducer, converting the signal into a form where it can ultimately trigger a change in the state or activity of a cell.
J. Biol. Chem. 267, 487-493 (1992)[PubMed:1370449]
Normal membrane expression of the T cell receptor (TCR) depends on the coordinated synthesis and assembly of all seven proteins composing the complex, i.e. the TCR alpha and beta chains, the CD3 gamma, delta, and epsilon chains, and the zeta-zeta or zeta-eta dimer. In an experimental TCR membrane-defective T cell variant (Sussman, J. L., Bonifacino, J. S., Lippincott-Schwartz, J., Weissman, A. M., Saito, T., Klausner, R. D., and Ashwell, J. D. (1988) Cell 52, 85-95) and in two siblings whose lymphocytes express only a low level of the TCR/CD3 complex (Alarcon, B., Berkhout, B., Breitmeyer, J., and Terhorst, C. (1988) N. Engl. J. Med. 319, 1203-1208), a defect in zeta chain synthesis and/or assembly was thought to account for the defective membrane synthesis of the whole complex. We report on another immunodeficient patient whose T lymphocytes express the T cell receptor at one-tenth of normal fluorescence intensity and are not triggered to proliferate in vitro by anti-CD3 or anti-CD2 antibodies. Biochemical analysis of the patient's surface-iodinated peripheral blood lymphocytes failed to detect TCR alpha and beta, or CD3 gamma, delta, and epsilon proteins but revealed the presence of the zeta homodimer (probably as a result of the high proportion of natural killer cells). In the cytoplasm, TCR alpha and beta proteins and the zeta chain were detected, but, using monoclonal anti-CD3 antibodies, the CD3 gamma, delta, and epsilon chains were not. In addition, the CD3 epsilon chain was not detected with polyclonal antiserum in a very sensitive Western blotting detection system. The zeta chain was shown to be synthesized by the patient's T and natural killer cells. Northern blot analysis revealed normal levels of normal-size TCR beta and CD3 gamma, delta gene-specific mRNAs and decreased levels of TCR alpha mARN; CD3 epsilon gene transcripts were of abnormal size and present in lower than normal amounts. These findings suggest that this defect in T cell receptor-CD3 expression involves a mutation in the CD3 epsilon gene leading to the synthesis of an abnormal and unstable CD3 epsilon subunit.
Interacting selectively and non-covalently with a SH3 domain (Src homology 3) of a protein, small protein modules containing approximately 50 amino acid residues found in a great variety of intracellular or membrane-associated proteins.
Evidence
1:
Inferred from Physical InteractionUniProtKB
How membrane receptors initiate signal transduction upon ligand binding is a matter of intense scrutiny. The T cell receptor complex (TCR-CD3) is composed of TCR alpha/beta ligand binding subunits bound to the CD3 subunits responsible for signal transduction. Although it has long been speculated that TCR-CD3 may undergo a conformational change, confirmation is still lacking. We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3 epsilon and results in recruitment of the adaptor protein Nck. This occurs earlier than and independently of tyrosine kinase activation. Finally, by interfering with Nck-CD3 epsilon association in vivo, we demonstrate that TCR-CD3 recruitment of Nck is critical for maturation of the immune synapse and for T cell activation.
Combining with an extracellular or intracellular signal and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity.
The TCR/CD3 complex is composed of six subunits which are expressed on the cell surface in a coordinate fashion after assembly in the endoplasmic reticulum (ER). The TCR/CD3 complex is assembled after a series of pairwise interactions involving the formation of dimers of CD3 epsilon with either CD3 gamma or CD3 delta. These dimers assemble with TCR alpha and TCR beta chains, and finally, the CD3 zeta homodimer is added to allow export of the full complex from the ER. A model has been proposed suggesting that during assembly the CD3 epsilon/CD3 gamma dimer interacts exclusively with TCR beta and the CD3 epsilon/CD3 delta dimer with TCR alpha to form a complex with a single TCR alpha/beta heterodimer. We show in this study, by immunoprecipitation and two-dimensional gel electrophoresis, that in the human T cell line Jurkat as well as in total human thymocytes, this preferential interaction does not occur and instead, the CD3 epsilon/CD3 gamma and CD3 epsilon/CD3 delta dimers associate with both TCR chains simultaneously and indistinctly. These data are confirmed by the analysis of the TCR alpha-negative T cell line MOLT-4 in which TCR beta is found separately associated with CD3 epsilon/CD3 gamma and with CD3 epsilon/CD3 delta dimers. Indirectly, our results support a model of stoichiometry in which two TCR alpha/beta heterodimers are present in a TCR/CD3 complex. Furthermore, immunoprecipitation with anti-CD3 gamma and anti-CD3 delta antibodies from 1% NP40 and 1% Brij96 cell lysates showed that these subunits form independent partial complexes which are cross-linked through the CD3 zeta homodimer. This suggests that CD3 zeta mediates the interaction between both TCR alpha/beta heterodimers contained in the double TCR complex. Further proof for this hypothesis is obtained after analysis of a Jurkat cell transfectant containing a point mutation in the transmembrane domain of TCR beta that impairs the association of CD3 zeta. In this mutant cell line, unlike a control line with wild-type TCR beta, the CD3 gamma- and CD3 delta-containing complexes were found completely independent. Altogether, these results support a model of TCR/CD3 assembly and stoichiometry in which two TCR-alpha/beta heterodimers form two hemicomplexes containing either CD3 epsilon/gamma or CD3 epsilon/delta dimers which become associated via the CD3 zeta homodimer.
A series of molecular signals initiated by activation of a receptor on the surface of a cell. The pathway begins with binding of an extracellular ligand to a cell surface receptor, or for receptors that signal in the absence of a ligand, by ligand-withdrawal or the activity of a constitutively active receptor. The pathway ends with regulation of a downstream cellular process, e.g. transcription.
How membrane receptors initiate signal transduction upon ligand binding is a matter of intense scrutiny. The T cell receptor complex (TCR-CD3) is composed of TCR alpha/beta ligand binding subunits bound to the CD3 subunits responsible for signal transduction. Although it has long been speculated that TCR-CD3 may undergo a conformational change, confirmation is still lacking. We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3 epsilon and results in recruitment of the adaptor protein Nck. This occurs earlier than and independently of tyrosine kinase activation. Finally, by interfering with Nck-CD3 epsilon association in vivo, we demonstrate that TCR-CD3 recruitment of Nck is critical for maturation of the immune synapse and for T cell activation.
A series of molecular signals that proceeds with an activated receptor promoting the exchange of GDP for GTP on the alpha-subunit of an associated heterotrimeric G-protein complex. The GTP-bound activated alpha-G-protein then dissociates from the beta- and gamma-subunits to further transmit the signal within the cell. The pathway begins with receptor-ligand interaction, or for basal GPCR signaling the pathway begins with the receptor activating its G protein in the absence of an agonist, and ends with regulation of a downstream cellular process, e.g. transcription.
J. Biol. Chem. 270, 30635-30642 (1995)[PubMed:8530500]
Engagement of the T cell receptor (TCR).CD3 complex results in the induction of multiple intracellular events, with protein tyrosine kinases playing a pivotal role in their initiation. Biochemical studies also exist suggesting the involvement of heterotrimeric GTP-binding proteins (G proteins); however, the functional consequence of this participation in TCR.CD3-mediated signaling is unresolved. Here, we report TCR.CD3-mediated guanine nucleotide exchange among the 42-kDa G protein alpha subunits of the G alpha q/11 family, their physical association with CD3 epsilon, and the G alpha 11-dependent activation of phospholipase C beta. Protein tyrosine kinase inhibitors, however, abrogate TCR.CD3-mediated G protein activation. Quite interesting is the observation that cells transfected with a function-deficient mutant of G alpha 11 display diminished tyrosine phosphorylation of TCR.CD3 zeta and epsilon chains, as well as ZAP-70, upon anti-CD3 antibody triggering. These data indicate the involvement of the G alpha q/11 family in TCR.CD3 signaling at a step proximal to the receptor and suggest a reciprocal regulation between tyrosine kinases and G proteins in T cells.
Any process that activates or increases the frequency, rate, or extent of interferon-gamma production. Interferon-gamma is also known as type II interferon.
Any process that activates or increases the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of interleukin-2.
How membrane receptors initiate signal transduction upon ligand binding is a matter of intense scrutiny. The T cell receptor complex (TCR-CD3) is composed of TCR alpha/beta ligand binding subunits bound to the CD3 subunits responsible for signal transduction. Although it has long been speculated that TCR-CD3 may undergo a conformational change, confirmation is still lacking. We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3 epsilon and results in recruitment of the adaptor protein Nck. This occurs earlier than and independently of tyrosine kinase activation. Finally, by interfering with Nck-CD3 epsilon association in vivo, we demonstrate that TCR-CD3 recruitment of Nck is critical for maturation of the immune synapse and for T cell activation.
CD3 gamma, delta, epsilon, and zeta proteins together with the pre-TCR alpha-chain (pT alpha) and a rearranged TCR beta-chain assemble to form the pre-TCR that controls the double negative (DN) to double positive (DP) stages of thymopoiesis. The CD3 proteins are expressed before pT alpha and TCR beta-chains in prothymocytes and are expressed intracellularly in precursor NK cells, suggesting that the CD3 complex may function independent of pT alpha and TCR beta. In this report, both the role of CD3 epsilon exclusively, and the role of CD3 proteins collectively, in thymocyte and NK cell development were examined. In a mouse strain termed E delta P, a neomycin cassette inserted within the CD3 epsilon promoter abolishes CD3 epsilon and delta expression and also abolishes CD3 gamma expression in all but a small minority (< or =1%) of prothymocytes. These prothymocytes became deficient in CD3 epsilon alone upon reconstitution of CD3 delta expression and were severely, but not completely, arrested at the DN stage, as small numbers of double positive thymocytes were detected. In de facto CD3 gamma delta epsilon zeta(null) mice generated by crossing the epsilon delta P mice with CD3 zeta-/- mice, thymopoiesis were arrested at the CD44-CD25+ DN stage as observed in RAG-/- mice, DJ and VDJ recombination at the TCR beta locus was functional, and normal numbers of NK cells were detected. Together, the findings demonstrate that during thymocyte development, the CD3 complex collectively is not essential until the critical CD44-CD25+ DN stage in which pre-TCR begins to function, whereas CD3 epsilon is critical for the assembly of pre-TCR. Moreover, CD3 proteins are dispensable for NK cell development.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao 21, 421-424 (1999)[PubMed:12567487]
OBJECTIVE: To study the role of bcl-2 gene overexpression in T lymphocyte apoptosis mediated by CD8 epsilon chimera molecule. METHODS: The cells expressed CD8 epsilon chimera molecule were transfected with a bcl-2 expression vector. The cells with Bcl-2 overexperssion were selected by G418 and limited dilution, and then treated with anti-CD8 antibody. The cell death was evaluated with flow cytometry. RESULTS: It was shown that there were only 2.6% of cells with Bcl-2 overexpression died by apoptosis. Comparing with Jurkat and TJK cells without Bcl-2 expression, in which there were 6.1% and 33.7% of cell death respectively, suggesting that Bcl-2 overexpression remarkbly inhibited apoptosis of the T lymphocytes mediated by CD8 epsilon chimera molecule. CONCLUSIONS: Bcl-2 overexpression could block T lymphocyte apoptosis mediated by CD3 epsilon molecule and the mechanisms remained to be clarified in detail.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a nutrient stimulus.
The T-cell receptor (TCR) is composed of two glycoproteins (alpha and beta or gamma and delta) associated with four invariant polypeptides (CD3-gamma, delta, epsilon and zeta). The majority of TCR/CD3 complexes contain six polypeptide chains, and although there is some flexibility in the complex subunit stoichiometry the CD3-epsilon chain is central to CD3 core assembly and full complex formation. We have described previously defective expression of the TCR/CD3 complex in an immunodeficient child. We now report that two independent CD3-epsilon gene mutations present in the parents have segregated in the patient, leading to defective CD3-epsilon chain synthesis and preventing normal association and membrane expression of the TCR/CD3 complex.
The change in morphology and behavior of a mature or immature T cell resulting from exposure to a mitogen, cytokine, chemokine, cellular ligand, or an antigen for which it is specific.
How membrane receptors initiate signal transduction upon ligand binding is a matter of intense scrutiny. The T cell receptor complex (TCR-CD3) is composed of TCR alpha/beta ligand binding subunits bound to the CD3 subunits responsible for signal transduction. Although it has long been speculated that TCR-CD3 may undergo a conformational change, confirmation is still lacking. We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3 epsilon and results in recruitment of the adaptor protein Nck. This occurs earlier than and independently of tyrosine kinase activation. Finally, by interfering with Nck-CD3 epsilon association in vivo, we demonstrate that TCR-CD3 recruitment of Nck is critical for maturation of the immune synapse and for T cell activation.
A series of molecular signals initiated by the binding of an extracellular ligand to a receptor on the surface of the target cell where the receptor possesses tyrosine kinase activity, and ending with regulation of a downstream cellular process, e.g. transcription.
J. Biol. Chem. 270, 30635-30642 (1995)[PubMed:8530500]
Engagement of the T cell receptor (TCR).CD3 complex results in the induction of multiple intracellular events, with protein tyrosine kinases playing a pivotal role in their initiation. Biochemical studies also exist suggesting the involvement of heterotrimeric GTP-binding proteins (G proteins); however, the functional consequence of this participation in TCR.CD3-mediated signaling is unresolved. Here, we report TCR.CD3-mediated guanine nucleotide exchange among the 42-kDa G protein alpha subunits of the G alpha q/11 family, their physical association with CD3 epsilon, and the G alpha 11-dependent activation of phospholipase C beta. Protein tyrosine kinase inhibitors, however, abrogate TCR.CD3-mediated G protein activation. Quite interesting is the observation that cells transfected with a function-deficient mutant of G alpha 11 display diminished tyrosine phosphorylation of TCR.CD3 zeta and epsilon chains, as well as ZAP-70, upon anti-CD3 antibody triggering. These data indicate the involvement of the G alpha q/11 family in TCR.CD3 signaling at a step proximal to the receptor and suggest a reciprocal regulation between tyrosine kinases and G proteins in T cells.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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