* 186780
CD247 ANTIGEN; CD247
Alternative titles; symbols
CD3 ANTIGEN, ZETA SUBUNIT; CD3Z
CD3-ZETA
T-CELL ANTIGEN RECEPTOR COMPLEX, ZETA SUBUNIT OF CD3; TCRZ
HGNC Approved Gene Symbol: CD247
Cytogenetic location: 1q24.2 Genomic coordinates (GRCh38) : 1:167,430,640-167,518,529 (from NCBI)
Gene-Phenotype Relationships
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q24.2 | ?Immunodeficiency 25 | 610163 | Autosomal recessive | 3 |
TEXT
Cloning and Expression
Weissman et al. (1986) used an antiserum raised against the mouse zeta subunit of the T-cell antigen receptor to identify a previously unrecognized component of the human T-cell antigen receptor. This human protein is T-cell specific and biochemically similar to the murine zeta polypeptide, which has a molecular weight of 16K. The zeta chain, which, like the epsilon chain, is nonglycosylated, exists in the T-cell receptor molecule as a disulfide-linked homodimer.
Weissman et al. (1988) cloned a cDNA encoding the zeta chain of the murine T-cell antigen receptor. The predicted protein sequence suggested a structure distinct from those of any of the previously described receptor subunits.
As indicated by Clevers et al. (1988), the T-cell receptor alpha/beta and gamma/delta heterodimers are noncovalently associated with the CD3-gamma (186740), -delta (186790), -epsilon (186830), and -zeta proteins, together forming the T-cell receptor-CD3 complex. Weissman et al. (1988) used the cDNA for the murine zeta gene as a probe to isolate cDNAs encoding the human CD3Z gene. Comparison of the human and murine genes showed a high degree of conservation, including conservation in the nucleotide sequence of the 5-prime and 3-prime untranslated regions. No significant sequence and structural homology was found, however, with the previously characterized invariant delta, gamma, and epsilon chains of the T-cell receptor.
Gene Function
The zeta chain of the T-cell antigen receptor plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways. Caplan et al. (1995) presented evidence that the zeta chain, while expressed on the T-cell surface, is associated with the cytoskeletal matrix. A 42-amino acid region in the intracytoplasmic domain of the zeta chain proved crucial for maximal interaction between zeta chain and the cytoskeleton.
CD4 (186940) binds to relatively invariant sites on class II major histocompatibility complex (MHC) molecules outside the peptide-binding groove, which interacts with the T-cell receptor (TCR). CD4 enhances T-cell sensitivity to antigen and binds to LCK (153390), which phosphorylates CD3Z. Instead of clustering in a cap at the interface with an antigen-presenting cell (APC), some signaling molecules involved in T-cell recognition segregate into distinct areas to form a SMAC (supramolecular activation cluster), contributing to the immunologic synapse (see Grakoui et al. (1999)). Using T-cell lines transfected with green fluorescent protein-fused CD4 or CD3Z and 3-dimensional video microscopy, Krummel et al. (2000) showed that in response to peptide-loaded APC, CD3Z and CD4 initially cluster in the contact area between the T cell and APC coincident with intracellular calcium mobilization. Stable immunologic synapse formation was modulated by peptide concentration and compromised by blocking the calcium increase or cytoskeletal rearrangement. The authors determined that CD3Z remains at the center of the interface while CD4 moves to the periphery. Blocking with anti-TCR prevented CD3Z accumulation and inhibited calcium mobilization. The data suggested that instead of stabilizing TCR-MHC complexes, CD4 functions to initiate or augment the early phase of T-cell activation.
Mapping
The CD3Z gene was localized by Weissman et al. (1988) to the centromeric region of chromosome 1 by study of somatic cell hybrids and by in situ hybridization, emphasizing the fact that it is a distinct genetic component of the T-cell receptor (the CD3D, CD3G, and CD3E genes are clustered within 300 kb of each other on 11q23). The gene was assigned to 1p22.1-q21.1. Baniyash et al. (1989) mapped the homologous gene in the mouse to chromosome 1. Sturm et al. (1995) mapped the human OTF1 gene (164175) to 1q22-q23 by fluorescence in situ hybridization. The physical linkage of the CD3Z gene to the OTF1 transcription unit indicates that CD3Z is also located at 1q22-q23.
Molecular Genetics
Rieux-Laucat et al. (2006) described a 4-month-old boy with primary T-cell immunodeficiency (IMD25; 610163) who was found to have a homozygous germline Q70X mutation in the CD3Z gene (186780.0001). CD3-zeta is necessary for the development and function of T cells. Some of the patient's T cells had low levels of the T-cell receptor-CD3 complex and carried the Q70X mutation on both alleles of the CD3Z gene, whereas other T cells had normal levels of the complex and bore the Q70X mutation on only 1 allele of CD3Z, plus 1 of 3 heterozygous somatic mutations of CD3Z on the other allele (186780.0002-186780.0004), allowing expression of poorly functional T-cell receptor-CD3 complexes. Thus the patient had both inherited and somatic CD3Z mutations as the basis of the T-cell deficiency.
Rieux-Laucat et al. (2006) noted that the finding of somatic mutations of a germline mutation in the CD3Z gene recalled somatic mutations of germline mutations of the adenosine deaminase gene (608958), the interleukin-2 receptor gamma-c gene (IL2RG; 308380), the recombination-activating gene-1 (RAG1; 179615), the Wiskott-Aldrich syndrome protein (301000), and the NEMO gene (300248). These somatic changes could cause the mutant gene to revert to a wildtype gene or to a sequence compatible with expression of the corresponding protein. In the patient of Rieux-Laucat et al. (2006), these somatic mutations occurring in the initially mutated codon were probably not due to a mutation hotspot related to genomic instability, since these variants were not found in other cell types from the patient. Furthermore, the T cells with normal levels of the T-cell receptor-CD3 complex were polyclonal, and each of the 3 somatic variants of CD3Z was found in different populations of T cells, each with a distinct rearrangement of V(beta) genes. This result indicated that the somatic mutations in CD3Z probably occurred before the VDJ recombination process in T-cell progenitors. The somatic mutations partially corrected the CD3Z deficiency, providing an example of the modulation of T-cell immunodeficiency by somatic mutations and of the selection of clones with such mutations.
Animal Model
Class I MHC molecules, known to be important for immune responses to antigen, are expressed also by neurons that undergo activity-dependent, long-term structural and synaptic modifications. Huh et al. (2000) showed that in mice genetically deficient for cell surface class I MHC, due to deletion of either TAP1 (170260) or beta-2-microglobulin (109700), or for the class I MHC receptor component CD3Z, refinement of connections between retina and central targets during development is incomplete. In the hippocampus of adult mutants, N-methyl-D-aspartate receptor-dependent long-term potentiation is enhanced, and long-term depression is absent. Specific class I MHC mRNAs are expressed by distinct mosaics of neurons, reflecting a potential for diverse neuronal functions. These results demonstrated an important role for these molecules in the activity-dependent remodeling and plasticity of connections in the developing and mature mammalian central nervous system.
In mice chronically exposed to antigens of Porphyromonas gingivalis, Bronstein-Sitton et al. (2003) observed that Ifng (147570)-dependent Tcrz downregulation, due to lysosomal degradation, and impaired in vitro T-cell function occurred in a way similar to that reported in a number of infectious, autoimmune, and cancer pathologies. The in vitro findings correlated with a deficient in vivo response, as assessed by reduced immunity to influenza virus infection. Normal immune function and Tcrz expression were regained after the cessation of chronic antigen exposure.
By in situ hybridization of wildtype mouse retina, Xu et al. (2010) showed that Cd3-zeta was preferentially expressed in the retinal ganglion cell (RGC) layer. In Cd3-zeta -/- mice, the kinetics of RGC dendritic elimination was markedly reduced, and the number of dendritic protrusions was significantly increased during early postnatal development. These defects could be mimicked in wildtype mice by applying glutamate receptor (GLUR; see 138248) antagonists. Disruption of RGC synaptic activity and dendritic motility was associated with a failure of eye-specific segregation of RGC axon projections to the central nervous system. Xu et al. (2010) concluded that CD3-zeta regulates synaptic wiring and selectively impairs GLUR-mediated synaptic activity in retina during development.
ALLELIC VARIANTS 4 Selected Examples):
.0001 IMMUNODEFICIENCY 25 (1 patient)
SNP: rs74315290, gnomAD: rs74315290, ClinVar: RCV000013586
In a 4-month-old boy of Caribbean origin with primary T-cell immunodeficiency (IMD25; 610163), Rieux-Laucat et al. (2006) identified homozygosity for a gln70-to-stop (Q70X) nonsense mutation in the CD3Z gene. The premature stop codon was located within the first ITAM domain, immediately upstream from the first YXXL motif, precluding expression of all ITAM motifs and thus any interaction with the tyrosine kinase ZAP70 (176947). The boy's mother was heterozygous for the Q70X mutation. The patient's other T cells had normal levels of the CD3 complex and bore the Q70X mutation on only 1 allele of CD3Z, plus 1 of 3 heterozygous somatic mutations of CD3Z on the other allele, allowing expression of poorly functional T-cell receptor-CD3 complexes. The heterozygous somatic mutations of CD3Z were Q70W (186780.0002), Q70L (186780), and Q70Y (186780).
.0002 IMMUNODEFICIENCY 25, SOMATIC
ClinVar: RCV000013587
Rieux-Laucat et al. (2006) described a child with primary T-cell immunodeficiency (IMD25; 610163) who had a homozygous germline mutation (Q70X; 186780.0001) on some T cells, but on other T cells had heterozygosity for the Q70X mutation in combination with 1 of 3 somatic mutations, i.e., Q70W, Q70L (186780.0003), or Q70Y (186780.0004).
.0003 IMMUNODEFICIENCY 25, SOMATIC
SNP: rs193922740, gnomAD: rs193922740, ClinVar: RCV000013588
Rieux-Laucat et al. (2006) described a child with primary T-cell immunodeficiency (IMD25; 610163) who had a homozygous germline mutation (Q70X; 186780.0001) on some T cells, but on other T cells had heterozygosity for the Q70X mutation in combination with 1 of 3 somatic mutations, i.e., Q70W (186780.0002), Q70L, or Q70Y (186780.0004).
.0004 IMMUNODEFICIENCY 25, SOMATIC
SNP: rs193922741, gnomAD: rs193922741, ClinVar: RCV000013589
Rieux-Laucat et al. (2006) described a child with primary T-cell immunodeficiency (IMD25; 610163) who had a homozygous germline mutation (Q70X; 186780.0001) on some T cells, but on other T cells had heterozygosity for the Q70X mutation in combination with 1 of 3 somatic mutations, i.e., Q70W (186780.0002), Q70L (186780.0003), or Q70Y.
REFERENCES
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Baniyash, M., Hsu, V. W., Seldin, M. F., Klausner, R. D. The isolation and characterization of the murine T cell antigen receptor zeta chain gene. J. Biol. Chem. 264: 13252-13257, 1989. [PubMed: 2787796]
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Bronstein-Sitton, N., Cohen-Daniel, L., Vaknin, I., Ezernitchi, A. V., Leshem, B., Halabi, A., Houri-Hadad, Y., Greenbaum, E., Zakay-Rones, Z., Shapira, L., Baniyash, M. Sustained exposure to bacterial antigen induces interferon-gamma-dependent T cell receptor zeta down-regulation and impaired T cell function. Nature Immun. 4: 957-964, 2003. [PubMed: 14502285] [Full Text: https://doi.org/10.1038/ni975]
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Caplan, S., Zeliger, S., Wang, L., Baniyash, M. Cell-surface-expressed T-cell antigen-receptor epsilon chain is associated with the cytoskeleton. Proc. Nat. Acad. Sci. 92: 4768-4772, 1995. [PubMed: 7761399] [Full Text: https://doi.org/10.1073/pnas.92.11.4768]
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Clevers, H., Alarcon, B., Wileman, T., Terhorst, C. The T cell receptor/CD3 complex: a dynamic protein ensemble. Annu. Rev. Immun. 6: 629-662, 1988. [PubMed: 3289580] [Full Text: https://doi.org/10.1146/annurev.iy.06.040188.003213]
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Grakoui, A., Bromley, S. K., Sumen, C., Davis, M. M., Shaw, A. S., Allen, P. M., Dustin, M. L. The immunological synapse: a molecular machine controlling T cell activation. Science 285: 221-227, 1999. [PubMed: 10398592] [Full Text: https://doi.org/10.1126/science.285.5425.221]
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Huh, G. S., Boulanger, L. M., Du, H., Riquelme, P. A., Brotz, T. M., Shatz, C. J. Functional requirement for class I MHC in CNS development and plasticity. Science 290: 2155-2159, 2000. [PubMed: 11118151] [Full Text: https://doi.org/10.1126/science.290.5499.2155]
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Krummel, M. F., Sjaastad, M. D., Wulfing, C., Davis, M. M. Differential clustering of CD4 and CD3-zeta during T cell recognition. Science 289: 1349-1352, 2000. [PubMed: 10958781] [Full Text: https://doi.org/10.1126/science.289.5483.1349]
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Rieux-Laucat, F., Hivroz, C., Lim, A., Mateo, V., Pellier, I., Selz, F., Fischer, A., Le Deist, F. Inherited and somatic CD3-zeta mutations in a patient with T-cell deficiency. New Eng. J. Med. 354: 1913-1921, 2006. [PubMed: 16672702] [Full Text: https://doi.org/10.1056/NEJMoa053750]
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Sturm, R. A., Eyre, H. J., Baker, E., Sutherland, G. R. The human OTF1 locus which overlaps the CD3Z gene is located at 1q22-q23. Cytogenet. Cell Genet. 68: 231-232, 1995. [PubMed: 7842742] [Full Text: https://doi.org/10.1159/000133919]
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Weissman, A. M., Baniyash, M., Hou, D., Samelson, L. E., Burgess, W. H., Klausner, R. D. Molecular cloning of the zeta chain of the T cell antigen receptor. Science 239: 1018-1021, 1988. [PubMed: 3278377] [Full Text: https://doi.org/10.1126/science.3278377]
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Weissman, A. M., Hou, D., Orloff, D. G., Modi, W. S., Seuanez, H., O'Brien, S. J., Klausner, R. D. Molecular cloning and chromosomal localization of the human T-cell receptor zeta chain: distinction from the molecular CD3 complex. Proc. Nat. Acad. Sci. 85: 9709-9713, 1988. [PubMed: 2974162] [Full Text: https://doi.org/10.1073/pnas.85.24.9709]
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Weissman, A. M., Samelson, L. E., Klausner, R. D. A new subunit of the human T-cell antigen receptor complex. Nature 324: 480-482, 1986. [PubMed: 3785426] [Full Text: https://doi.org/10.1038/324480a0]
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Xu, H., Chen, H., Ding, Q., Xie, Z.-H., Chen, L., Diao, L., Wang, P., Gan, L., Crair, M. C., Tian, N. The immune protein CD3-zeta is required for normal development of neural circuits in the retina. Neuron 65: 503-515, 2010. [PubMed: 20188655] [Full Text: https://doi.org/10.1016/j.neuron.2010.01.035]
Victor A. McKusick - updated : 5/24/2006
Paul J. Converse - updated : 10/3/2003
Ada Hamosh - updated : 1/5/2001
Paul J. Converse - updated : 8/24/2000
mgross : 6/20/2011
terry : 6/14/2011
terry : 8/24/2006
carol : 6/7/2006
carol : 6/7/2006
carol : 6/7/2006
terry : 5/24/2006
alopez : 10/16/2003
mgross : 10/3/2003
carol : 1/5/2001
carol : 8/29/2000
mgross : 8/24/2000
psherman : 8/24/1999
mark : 4/19/1997
mark : 6/16/1995
mimadm : 5/10/1995
supermim : 3/16/1992
carol : 7/13/1990
supermim : 3/20/1990
ddp : 10/27/1989