Alternative titles; symbols
HGNC Approved Gene Symbol: CD3D
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38): 11:118,338,954-118,342,705 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.3 | Immunodeficiency 19, severe combined | 615617 | Autosomal recessive | 3 |
The T-cell antigen receptor has multiple components: alpha (see 186880) and beta (see 186930) subunits, which are joined by disulfide bonds, and the 4 subunits of T3, epsilon (CD3E; 186830), delta (CD3D), gamma (CD3G; 186740), and zeta (CD3Z; 186780).
The T cell-receptor complex consists of the alpha and beta or gamma and delta variant chains, paired as mutationally exclusive heterodimers, in association with the invariant chains CD3G, CD3D, CD3E, and CD3Z. T cells with alpha (TCRA) and beta (TCRB) chains are referred to as alpha/beta T cells, and those with gamma (TCRG; see 186970) and delta (TCRD; see 186810) chains are called gamma/delta T cells. During development, the CD3 protein complex plays an important part in the transition of thymocytes from immature precursors to the final mature CD4+ or CD8+ single-positive T cell. Selective deficiency of any 1 of the 4 CD3 components in mice, achieved by gene knockout, causes mild to severe, although incomplete, blockage of T cell development. Similarly, CD3G or CD3E deficiency in human beings brings about a partial arrest of T-cell maturation and moderate immunodeficiency; see 186740 and 186830, respectively, for description of specific mutations (summary by Dadi et al., 2003).
In the thymus, immature thymocytes recognizing self major histocompatibility complex are selected to survive and differentiate through positive selection. Conversely, overtly self-reactive thymocytes are removed through negative selection. Thymocyte development in CD3D-deficient mice is arrested at the CD4/CD8 double-positive stage with markedly diminished expression of the T-cell antigen receptor (TCR; see 186880). Delgado et al. (2000) reported that activation of ERK (MAPK3; 601795) but not p38 (MAPK14; 600289), which regulates negative selection, or JNK1 (MAPK8; 601158), is also deficient in these mice. They showed that positive selection with differentiation into more mature thymocytes, as well as TCR, CD5 (153340), and CD69 (107273) expression and ERK activation, is rescued by the expression of CD3D with or without a cytoplasmic tail, following TCR engagement. Although SLP76 (LCP2; 601603) and VAV (164875) phosphorylation was unimpaired in CD3D-deficient thymocytes, phosphorylation of LAT (602354) was severely diminished. Again, expression of tailless CD3D restored LAT tyrosine phosphorylation and other downstream events. The presence of tailless CD3D also restored the levels of tyrosine-phosphorylated CD3Z in lipid rafts (see 604597 and Simons and Ikonen (1997)), to which LAT is constitutively localized, possibly explaining the signaling defects downstream of LAT phosphorylation.
Dadi et al. (2003) examined the thymi of CD3D-deficient infants and found arrest in T-cell development at the pre-TCR expression stage, with a nearly complete absence of circulating mature T cells and a complete absence of gamma/delta T cells. The results suggested that, unlike CD3E and CD3G, CD3D is essential for T-cell development. De Saint Basile et al. (2004) examined the thymus from a CD3D-deficient fetus and found that T-cell differentiation was blocked at entry into the double positive (CD4+/CD8+) stage with the accumulation of intermediate CD4-single positive cells. They concluded that CD3D is required during the early stages of human thymopoiesis.
Van den Elsen et al. (1986) demonstrated that the T3D gene is about 4 kb long and contains 5 exons.
By use of a cDNA clone in hybrid cells, van den Elsen et al. (1985) assigned the gene for the delta chain of the T3 T-cell antigen (OKT3) to 11q23-11qter. The mouse counterpart was found by parallel methods to be on chromosome 9. There may be functional significance to the fact that both this gene and THY1 (188230) map to chromosome 11q in man and chromosome 9 in mouse. The explanation does not reside in common evolutionary origin because they show no sequence homology. Rabbitts et al. (1985) confirmed the assignment on chromosome 11.
Using standard cloning techniques, together with field inversion gel electrophoresis, Tunnacliffe et al. (1987) demonstrated the close physical linkage of 3 CD3 genes. The genes for CD3-gamma and CD3-delta are situated close together, about 1.6 kb apart, organized in a head-to-head orientation. The CD3-gamma/CD3-delta gene pair is within 300 kb of the CD3-epsilon gene and therefore these genes form a tightly linked cluster on 11q23. The clustering may be significant in terms of their simultaneous activations during T-cell development. The separation of CD3E from CD3G/CD3D may be as little as 20 kb. By field inversion gel electrophoresis and molecular cloning, Tunnacliffe et al. (1988) found that the 3 genes lie within a stretch of 50 kb of DNA, oriented 3-prime--CD3G--5-prime:5-prime--CD3D--3-prime:3-prime--CD3E--5- prime.
Using 19 biotin-labeled probes in a study of 4 different translocations involving band 11q23, Rowley et al. (1990) found that CD3D was proximal to the breakpoint in all 4 and that PBGD (609806), THY1, SRPR (182180), and ETS1 (164720) were distal to the breakpoint. Hybridization with genomic DNA from a yeast clone containing yeast artificial chromosomes (YACs) that carried 320 kb of human DNA including the CD3D and CD3G genes showed that the YACs were split in all 4 translocations. Thus, the breakpoint in each of these translocations occurred within the 320 kb encompassed by these YACs.
In 3 members of a kindred with primary immunodeficiency-19 (IMD19; 615617) manifesting as T cell-negative, B cell-positive, natural killer (NK) cell-positive severe combined immunodeficiency (SCID) Dadi et al. (2003) identified a homozygous truncating mutation in the CD3D gene (R68X; 186790.0001).
In affected members of 2 consanguineous families with IMD19 presenting as T-, B+, NK+ SCID, De Saint Basile et al. (2004) identified homozygous mutations in the CD3D gene (186790.0001 and 186790.0002).
Gil et al. (2011) identified a homozygous splice-site mutation in the CD3D gene (IVS2+5G-A; 186790.0003) in 2 unrelated Ecuadorian children from nonconsanguineous parents who presented with IMD19. Both patients were T-alpha/beta negative, T-gamma/delta positive, B positive, and NK positive.
In 3 affected members of a kindred of Mennonite descent with primary immunodeficiency-19 (IMD19; 615617) manifesting as T-, B+, NK+ SCID, Dadi et al. (2003) identified a homozygous 202C-T transition in the CD3D gene, resulting in an arg68-to-ter (R68X) substitution in the extracellular domain of the protein. The 3 affected individuals were related as first cousins, each in a different sibship.
De Saint Basile et al. (2004) identified homozygosity for the R68X mutation in affected members of 2 consanguineous families with T-, B+, NK+ SCID. Both normal and mutated alleles were detected in the genomic DNA of the parents.
Yu et al. (2011) retrospectively studied a brother and sister with T-, B+, NK+ SCID who were homozygous for the R68X mutation. The patients presented with typical clinical features, including failure to thrive, diarrhea, and recurrent and/or opportunistic infections, including fungal and CMV. Both had lymphopenia and absence of circulating CD3+ T cells, as well as decreased T-cell proliferative responses. Both underwent bone marrow transplantation; 1 sib died shortly thereafter, whereas the other was alive and well at age 16 years.
In a patient with primary immunodeficiency-19 (IMD19; 615617) manifesting as T-, B+, NK+ SCID from a consanguineous family, de Saint Basile et al. (2004) identified homozygosity for a 279C-A transversion in exon 3 of the CD3D gene, resulting in a cys93-to-ter (C93X) substitution. Both normal and mutated alleles were detected in the genomic DNA of the parents and an unaffected sib.
Gil et al. (2011) reported 2 unrelated Ecuadorian male children from nonconsanguineous parents who presented at 13 and 5 months of age with primary immunodeficiency-19 (IMD19; 615617) manifesting as SCID and low CD3 expression. Both patients were T-alpha/beta negative, T-gamma/delta positive, B positive, and NK positive. The patients received haploidentical CD34 (142230)-positive stem cell transplants at ages 23 and 8 months, respectively. The latter patient died, probably due to cytomegalovirus found in multiple organs at necropsy, but the former was well at age 4 years. Sequencing of CD3D RNA revealed an in-frame deletion of exon 2, which encodes the extracellular Ig-like domain. Genomic DNA sequencing detected a homozygous G-A transition at position +5 in the 5-prime splice donor site of intron 2 (IVS2+5G-A; 186790.0003) of the CD3D gene. The parents of the patients were heterozygous carriers of the mutation and had a shared core CD3 haplotype, suggesting a shared founder mutation. Quantitative RT-PCR revealed a small amount of wildtype CD3D transcript in patient peripheral blood mononuclear cells, and Western blot analysis showed that patient T cells expressed half the normal level of CD3D. On a per-cell basis, patient T-alpha/beta and T-gamma/delta cells showed normal responses to mitogens, but they displayed reduced induction of CD69 (107273) and CD25 (IL2RA; 147730). Gil et al. (2011) concluded that the leaky IVS2+5G-A mutation reduced CD3D chains and blocked T-alpha/beta rather than T-gamma/delta selection.
Dadi, H. K., Simon, A. J., Roifman, C. M. Effect of CD3-delta deficiency on maturation of alpha/beta and gamma/delta T-cell lineages in severe combined immunodeficiency. New Eng. J. Med. 349: 1821-1828, 2003. Note: Erratum: New Eng. J. Med. 350: 1803 only, 2004. [PubMed: 14602880] [Full Text: https://doi.org/10.1056/NEJMoa031178]
de Saint Basile, G., Geissmann, F., Flori, E., Uring-Lambert, B., Soudais, C., Cavazzana-Calvo, M., Durandy, A., Jabado, N., Fischer, A., Le Diest, F. Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3. J. Clin. Invest. 114: 1512-1517, 2004. [PubMed: 15546002] [Full Text: https://doi.org/10.1172/JCI22588]
Delgado, P., Fernandez, E., Dave, V., Kappes, D., Alarcon, B. CD3-delta couples T-cell receptor signalling to ERK activation and thymocyte positive selection. Nature 406: 426-430, 2000. [PubMed: 10935641] [Full Text: https://doi.org/10.1038/35019102]
Gil, J., Busto, E. M., Garcillan, B., Chean, C., Garcia-Rodriguez, M. C., Diaz-Alderete, A., Navarro, J., Reine, J., Mencia, A., Gurbindo, D., Belendez, C., Gordillo, I., and 9 others. A leaky mutation in CD3D differentially affects alpha-beta and gamma-delta T cells and leads to a T-alpha/beta-T-gamma/delta+B+NK+ human SCID. J. Clin. Invest. 121: 3872-3876, 2011. [PubMed: 21926461] [Full Text: https://doi.org/10.1172/JCI44254]
Rabbitts, T. H., Lefranc, M. P., Stinson, M. A., Sims, J. E., Schroder, J., Steinmetz, M., Spurr, N. L., Solomon, E., Goodfellow, P. N. The chromosomal location of T-cell receptor genes and a T cell rearranging gene: possible correlation with specific translocations in human T cell leukaemia. EMBO J. 4: 1461-1465, 1985. [PubMed: 3875483] [Full Text: https://doi.org/10.1002/j.1460-2075.1985.tb03803.x]
Rowley, J. D., Diaz, M. O., Espinosa, R., III, Patel, Y. D., van Melle, E., Ziemin, S., Taillon-Miller, P., Lichter, P., Evans, G. A., Kersey, J. H., Ward, D. C., Domer, P. H., Le Beau, M. M. Mapping chromosome band 11q23 in human acute leukemia with biotinylated probes: identification of 11q23 translocation breakpoints with a yeast artificial chromosome. Proc. Nat. Acad. Sci. 87: 9358-9362, 1990. [PubMed: 2251277] [Full Text: https://doi.org/10.1073/pnas.87.23.9358]
Simons, K., Ikonen, E. Functional rafts in cell membranes. Nature 387: 569-572, 1997. [PubMed: 9177342] [Full Text: https://doi.org/10.1038/42408]
Tunnacliffe, A., Buluwela, L., Rabbitts, T. H. Physical linkage of three CD3 genes on human chromosome 11. EMBO J. 6: 2953-2957, 1987. [PubMed: 2826124] [Full Text: https://doi.org/10.1002/j.1460-2075.1987.tb02600.x]
Tunnacliffe, A., Olsson, C., Buluwela, L., Rabbitts, T. H. Organization of the human CD3 locus on chromosome 11. Europ. J. Immun. 18: 1639-1642, 1988. [PubMed: 2973415] [Full Text: https://doi.org/10.1002/eji.1830181027]
van den Elsen, P., Bruns, G., Gerhard, D. S., Pravtcheva, D., Jones, C., Housman, D., Ruddle, F. A., Orkin, S., Terhorst, C. Assignment of the gene coding for the T3-delta subunit of the T3--T-cell receptor complex to the long arm of human chromosome 11 and to mouse chromosome 9. Proc. Nat. Acad. Sci. 82: 2920-2924, 1985. [PubMed: 3857625] [Full Text: https://doi.org/10.1073/pnas.82.9.2920]
van den Elsen, P., Georgopoulos, K., Shepley, B.-A., Orkin, S., Terhorst, C. Exon/intron organization of the genes coding for the delta chains of the human and murine T-cell receptor/T3 complex. Proc. Nat. Acad. Sci. 83: 2944-2948, 1986. [PubMed: 2939461] [Full Text: https://doi.org/10.1073/pnas.83.9.2944]
Yu, G. P., Nadeau, K. C., Berk, D. R., de Sant Basile, G., Lambert, N., Knapnougel, P., Roberts, J., Kavanau, K., Dunn, E., Stiehm, E. R., Lewis, D. B., Umetsu, D. T., Puck, J. M., Cowan, M. J. Genotype, phenotype, and outcomes of nine patients with T-B+NK+ SCID. Pediat. Transplant. 15: 733-741, 2011. [PubMed: 21883749] [Full Text: https://doi.org/10.1111/j.1399-3046.2011.01563.x]