Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Anna Morath
  • Sumit Deswal
  • Wolfgang W. A. Schamel
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_613


 ζ;  CD247;  TCRζ


CD3ζ is a homodimer-forming type 1 transmembrane (TM) protein and is part of the T cell antigen receptor (TCR) complex along with TCRαβ, CD3γε, and CD3δε dimers expressed on the surface of T cells (Figs. 1 and 2). T cells are an important component of the vertebrate adaptive immune system that are activated via TCR by the peptides generated from infectious agents and presented on major histocompatibility complex (MHC) molecules on the surface of cells. CD3ζ possesses a small extracellular part, a TM region, and a long cytoplasmic part that contains three immunoreceptor tyrosine-based activation motifs (ITAMs), which correspond to the six tyrosines that get phosphorylated upon antigen binding to the extracellular part of TCRαβ. Phosphorylation subsequently activates several downstream signaling cascades. Hence, CD3ζ plays a vital role in the activation of a T cell. CD3ζ is also part of the pre-TCR in pre-T cells and the γδTCR in γδ T cells that contains TCRγδ instead of TCRαβ. In addition, CD3ζ is also expressed in other cell types and as a member of other receptor complexes. In experimental studies, CD3ζ is often tagged with fluorescent proteins for the study of TCR dynamics in the immune synapse.
CD3ζ, Fig. 1

Schematic representation of CD3ζ. CD3ζ possesses a small nine amino acid ectodomain, a TM region, and a long cytoplasmic domain (112 amino acids in human) with three ITAMs, each of which contains two tyrosines. The two CD3ζ chains are joined by a disulphide bond at the border of the extracellular and the TM regions

CD3ζ, Fig. 2

Structure of the TCR complex. The CD3ζζ dimer is a component of the TCR complex, which in addition contains CD3γε, CD3δε, and TCRαβ and is expressed on T cells of the immune system. TCRαβ are the ligand-binding subunits, while the CD3 chains aid in receptor assembly, transport to the cell surface, and in signal transmission. Important for assembly are the potentially charged amino acids in the TM region of the TCR

Historical Background

CD3ζ was first discovered in T cells as a component of the TCR in 1985 (Samelson et al. 1985) and as a part of the pre-TCR complex where it was shown to play an important role in T cell development. Later, it was also found to be a component of the activating receptors NK-cell protein 46 ( NKp46), NKp30, and the low affinity Fc receptor for IgG (FcγRIII), which are expressed by NK cells (Lanier et al. 1989). It was also found to be expressed in retinal ganglion cells, where it regulates neuronal development (Xu et al. 2010).

Evolution, Genomic Organization, and Protein Structure

The CD3ζ gene is evolutionarily related to other ITAM-containing proteins as highlighted by analysis of its exon–intron organization. The nucleotide sequence corresponding to each of the three CD3ζ ITAMs is encoded by two exons that are interrupted by a phase 0 intron at the same position (one amino acid after the first tyrosine of the ITAM). This indicates that these repeated motifs probably derive from triplication of an ancestral pair of exons, the product of which participates in the intracellular signaling by binding to tandem SH2 domain–containing proteins. Such exon–intron structure is also present in most of the other sequences coding for ITAMs. Therefore, a primitive two-exon set has probably undergone multiple rounds of duplication and transposition through evolution to give rise to the gene for CD3ζ by triplication and to various Ig-like (Ig-α, Ig-β, CD3γ, CD3δ, and CD3ε) or non-Ig-like (FcεRI-β, FcεRI-γ, DAP-12/KARAP) ectodomain-containing proteins through exon shuffling. It is speculated that the CD3ζ, FcεRI-γ, and DAP-12/KARAP polypeptide set might have branched off from the ancestor of the CD3εγδ set and lost the exon corresponding to the extracellular Ig domain. Therefore, CD3ζ probably shares both a common origin (an ancestral two-exon set) and a common function (recruiting SH2-containing signaling proteins) with the other ITAM-containing proteins found associated with immunoreceptors (Malissen 2003).

However, the CD3ζ chain differs from other TCR subunits in its genetic organization, chromosomal localization, and protein structure. The gene encoding the CD3ζ chain is found in the distal part of chromosome 1 in humans and mice. There is an alternatively spliced form, CD3η, in which exon 8 (zeta specific exon) is replaced with exon 9 (η specific exon) (Ohno and Saito 1990) (Fig. 3). In some circumstances, the TCR complex can contain heterodimers of CD3ζ/η or FcRγ. For example, following activation of the γδ T cells, FcRγ is expressed and is included in the γδTCR complex (Hayes and Love 2002), and in CD4CD8 double negative NK1.1+ T cells, FcRγ forms a heterodimer with CD3ζ which may drive these cells along NK cell lineage (Curnow et al. 1995).
CD3ζ, Fig. 3

Genomic organization of the human CD3ζ gene. The gene encoding CD3ζ is localized to the distal part of chromosome 1 and comprises a total of nine exons. CD3ζ is translated from the first eight exons while in an alternatively spliced form, CD3η, exon 8 is replaced with exon 9. The nucleotides location corresponding to each ITAM tyrosine is marked by Y in exons 3–8

At its N-terminus CD3ζ contains a signal peptide that targets protein translation to the endoplasmic reticulum. Since this peptide is cleaved cotranslationally, it is not present in mature CD3ζ. Unlike the other  CD3 subunits, CD3ζ has a very short ectodomain of nine amino acids and a long cytoplasmic tail (112 amino acids in human and 113 in mouse) and does not belong to the Ig supergene family. The short CD3ζ ectodomain is buried within the TCR complex, and its length, but not primary amino acid sequence, is highly conserved across orthologs. When this domain is artificially enlarged, the resulting TCR complex is distorted leading to a hyperactive phenotype and enhanced T cell activation (Minguet et al. 2008). So far, only the three-dimensional structure of the TM part of the CD3ζζ dimer has been solved by NMR studies (Call et al. 2006), which showed that the TM domain of CD3ζ adopts an α-helical structure (Fig. 4). The TM dimer interface is composed of both hydrophobic packing interactions and intermolecular hydrogen bonds and a potentially charged aspartic acid on each CD3ζ. A disulfide bond between the cysteine residues in the TM portion stabilizes the dimer, although it is not absolutely required for dimerization or assembly with the TCR. In its cytoplasmic domain, CD3ζ contains three ITAMs, which get phosphorylated upon antigenic stimulation. In contrast, CD3η contains 155 amino acids and only two ITAMs in its cytoplasmic domain.
CD3ζ, Fig. 4

NMR structure of CD3ζ transmembrane region. The TM domain of CD3ζ adopts an α-helical structure. The NMR structure was downloaded from protein data bank (PDB ID: 2HAC) and images prepared using the software MacPymol. The acidic residue aspartic acid is shown in the stick form. (a) is rotated by approximately 90° compared to (b)

Assembly and Membrane Organization

Only a fully assembled TCR complex is transported to the T cell plasma membrane, while individual subunits are most likely degraded in the endoplasmic reticulum. Thus, in T cells lacking CD3ζ, a TCRαβCD3εγεδ complex is only expressed at low levels on cell surface. CD3ζ is the last subunit to be associated with TCR complex and may only assemble to the other subunits in the Golgi, where it shields the lysosomal targeting sequence in CD3γ. Each of the CD3ζ, CD3ε, and CD3δ molecules possess an ionizable aspartic acid in their TM region, while CD3γ possesses a glutamic acid residue. Together, this gives six acidic residues in the TM region of the TCR complex. TCRβ and TCRα possess one and two basic residues, respectively, in their TM region. This gave rise to the speculation that each TCR complex might contain two TCRαβ dimers to balance the six acidic residues in the CD3εγεδζζ. However, several studies have suggested a stoichiometry of TCRαβCD3εγεδζζ (Schamel et al. 2005). Indeed, assembly of each of the three CD3 dimers with TCRαβ involves a trimeric interface between one basic and two acidic TM residues where CD3ζ associates with TCRα. So the basic TCR complex is monovalent, which then associates with other TCR complexes to give rise to TCR nanoclusters. TCR nanoclusters increase the avidity towards multimeric pMHC and thus provide the T cell with high sensitivity to detect minute numbers of antigenic peptides (Schamel et al. 2005, Molnár et al. 2012, Schamel and Alarcón 2013).

Phosphorylation and Internalization of CD3ζ

Following receptor ligation, CD3ζ is the most heavily tyrosine-phosphorylated subunit of the TCR. The phosphorylation pattern of CD3ζ has been a topic of intense debate. In Western blot experiments, several forms of CD3ζ can be observed depending upon its phosphorylation status. Among these, forms with an apparent molecular weight of 16, 21, and 23 kDa are the most prominent in reducing SDS-PAGE. The 16 kDa form represents nonphosphorylated CD3ζ. The 21 kDa form most likely represents CD3ζ phosphorylated at four tyrosines and is generated upon stimulation of T cells by low affinity self pMHC ligands or altered peptide ligands. The 23 kDa form results from phosphorylation of all the six tyrosines upon stimulation with high affinity foreign pMHC ligands. The order of phosphorylation of the different tyrosines and which four tyrosines are phosphorylated in 21 kDa form is not clear, as the results from different studies are contradictory. According to one study (Kersh et al. 1998), tyrosine 3 (Y3) and tyrosine 6 (Y6) are phosphorylated in resting T cells (Fig. 5a), most likely by the interaction of TCRαβ with low affinity self-peptides presented on MHC. Upon stimulation by high affinity foreign peptides on MHC, the phosphorylation of tyrosines follows a specific order as indicated in Fig. 5a. In a second study (van Oers et al. 2000), a different order of phosphorylation was proposed (Fig. 5b). The four membrane distal tyrosines are phosphorylated by low affinity self-pMHC interactions (the 21 kDa form of CD3ζ), and all tyrosines are phosphorylated only upon high affinity interaction with foreign pMHC (the 23 kDa form) as in the earlier study.
CD3ζ, Fig. 5

Phosphorylation pattern of CD3ζ. After different stimulation of the TCR, several distinct molecular weight forms of CD3ζ can be distinguished by reducing SDS-PAGE. There are two models (a and b) that explain to which phosphorylation forms they correspond. (a) In one model, tyrosine 3 (Y3) and tyrosine 6 (Y6) are phosphorylated in resting T cells. Upon stimulation by antigen, the phosphorylation of tyrosines follows a specific order as indicated. Only the high affinity agonist ligand results in full phosphorylation and generates 23 kDa CD3ζ form. (b) In another model, CD3ζ undergoes a stepwise phosphorylation that is initiated at Y6. Tyrosines 3–6 are phosphorylated by low affinity self-peptide-MHC interactions (21 kDa form) and all tyrosines are phosphorylated upon high affinity interaction with foreign peptide loaded on MHC (23 kDa)

CD3ζ has not been reported to undergo serine or threonine phosphorylation.

How the binding of pMHC ligand to the ectodomains of TCRαβ transmits the signal to the cytoplasmic tail of CD3ζ has not been resolved yet. In aqueous solution, the cytoplasmic tail of CD3ζ is unstructured, whereas in the presence of liposomes it exhibits a helical secondary structure. This lipid binding-dependent conformational change in CD3ζ could be one activation mechanism. In the preactivation state when CD3ζ is bound to the inner leaflet of the plasma membrane, it is resistant to phosphorylation by the  Src family tyrosine kinases. TCR engagement by pMHC ligands might force cytoplasmic tails to be released from the membrane, which now are accessible for phosphorylation by the kinases (Aivazian and Stern 2000; Gagnon et al. 2012). Another report proposes a change in the proximity of the CD3ζ juxtamembrane regions upon TCR triggering (Lee et al. 2015). In this model the CD3ζ dimers are separated in the resting TCR by their interaction with TCRα. Ligand binding to TCRαβ would induce a loosening of this interaction so that the CD3ζ dimers can come together.

Another possibility is that the TCR is in equilibrium between a resting and an active conformation (Swamy et al. 2016). CD3ζ tyrosines would only be accessible for phosphorylation in the active conformation. In resting state, cholesterol-binding to TCRβ favors the resting, inactive conformation. pMHC binding stabilizes the active conformation, hence makes the tyrosines accessible for phosphorylation (Minguet and Schamel 2008). Once signaling by the TCR is initiated, the influx of Ca2+ ions into the cytoplasm facilitates the dissociation of the CD3ζ cytoplasmic tail from the plasma membrane and sustains ITAM phosphorylation (Shi et al. 2013).

The TCR is constitutively internalized and recycled to the plasma membrane in naïve and activated T cells. Phosphorylation of the TCR upon activation by antigen binding leads to enhanced TCR downregulation from the cell surface. Cell surface TCRs lacking CD3ζ are endocytosed more rapidly than completely assembled receptors. CD3ζ may stabilize TCR expression on cell surface by blocking access to the internalization motifs on other CD3 subunits (D’Oro et al. 2002). On the other hand phosphorylated CD3ζ targets internalized TCR for ubiquitin-dependent degradation. Src-like adapter protein (SLAP) binds to internalized and phosphorylated CD3ζ via its SH2 domain in the endosomal compartment and mediates recruitment of the E3 ubiquitin ligase CBL (Casitas B-lineage lymphoma; also known as c-CBL), resulting in ubiquitylation of CD3ζ, thereby targeting the TCR for degradation. Another study suggests that phosphorylated CD3ζ accumulates in endosomes (Yudushkin and Vale 2010). This endosomal CD3ζ remained signaling competent and could possibly help to sustain long-term signaling in T cells.


The TCR complex plays a critical role in the immune response by activating the T cells which then help in the activation of B cells by releasing helper cytokines (helper T cells) or killing the target cell directly by inducing apoptosis. CD3ζ has two important functions: (1) assembly of the TCR complex in the ER/Golgi and transport to the cell surface, as a TCR complex lacking CD3ζ is mostly subjected to lysosomal degradation and (2) signaling, as the TCRαβ or TCRγδ dimer itself lacks the signaling motifs and relies on the CD3ε, CD3γ, CD3δ, and CD3ζ components for intracellular signaling. Each CD3ζ contains six tyrosines, helping in signal amplification. The tyrosines of the ITAM are phosphorylated by the Src family kinases Lck and Fyn. This leads to the recruitment of the tyrosine kinase  ZAP70 and Syk to the phospho-tyrosines via its tandem SH2 domains. In addition, the adaptor protein SAP and several other signaling proteins are recruited to phosphorylated CD3ζ ITAMs (Proust et al. 2012; Borroto et al. 2014).This initiates further downstream signaling and ultimately activation of the T cell.

A similar sequence of events takes place in the signal transduction downstream of pre-TCR in the developing pre-T cells. The signals are required for TCRα gene arrangement and further development of these cells. In addition, CD3ζ is expressed on pro-T cells. In pro-T cells CD3ζ was phosphorylated upon anti-CD3ε antibody stimulation, although no direct association between CD3ζ and other CD3 subunits was observed. CD3ζ-deficient mice have a decreased number of peripheral T cells, as will be discussed later.

Further, the small GTPase TC21, the microtubule end-binding protein EB1, and the GPCR-interacting protein β-arrestin 1 can bind to the nonphosphorylated ITAMs of CD3ζ (Delgado et al. 2009; Martín-Cófreces et al. 2012; Fernández-Arenas et al. 2014). These atypical interaction partners provide cell viability, control dynamics of the immune synapse, and play a role in TCR internalization.

Several studies have been performed to explore the role of the individual ITAMs in the different CD3 proteins in T cell development and function. According to one study, together the ITAMs in CD3ε, CD3γ, and CD3δ can provide normal TCR signal transmission in mature, peripheral T cells, and CD3ζ ITAMs play mainly a role in positive selection in the thymus (Pitcher et al. 2005b). However, in another study, expression of the mutant CD3ζ, which lacked Y1 and Y2, so that the 23 kDa form of CD3ζ could not be generated (Fig. 5), partially impaired negative selection and promoted the emergence of potentially autoreactive T cells (Pitcher et al. 2005a). Furthermore, contradicting results were obtained in a comprehensive study of all CD3 ITAMs (Holst et al. 2008). Mice with only six to two wild-type ITAMs developed a lethal, multiorgan autoimmune disease due to breakdown in central tolerance. The proliferation potential of cells was directly proportional to the number of ITAMs, whereas cytokine production was independent of the ITAM number. Thus, a high number of ITAMs in TCR amplifies the signaling that effects proliferation and ensures negative selection to prevent autoimmunity.

In resting human T cells, a portion of CD3ζ associates with the actin cytoskeleton. This interaction, mediated by a sequence in the C-terminus of CD3ζ, may be involved in the localization of the TCR into lipid raft structures and/or in TCR recycling. Some viral proteins, such as simian immunodeficiency virus Nef, bind the CD3ζ and downmodulate TCR. Such interaction seems to have evolved as an immune escape strategy for the virus. CD3ζ is also shown to interact with the transferrin receptor (TfR) and plays a role in T-cell activation via TfR stimulation. The TfR/CD3ζ complex is expressed on the cell surface independent of the expression of the other subunits of the TCR, and activation of this complex might be a signal-amplifying mechanism for T cells. Phosphorylated CD3ζ can bind to several SH2 domain–containing proteins which include adaptor proteins Shc and Grb2 and the p85 subunit of PI3K. SLAP-2, an SH2 domain–containing protein related to SLAP, binds to CD3ζ upon ligand binding and is a negative regulator of downstream signaling. CTLA-4, another negative regulator of the T-cell activation, binds to phospho-CD3ζ and prevents accumulation of the TCR in lipid rafts upon antigen binding.

In addition, CD3ζ is also expressed in cells other than T cells, for example, NK cells and neurons. In NK cells, CD3ζ is associated with NK FcγRIII (CD16) and may be necessary for efficient cell surface expression of this receptor complex. Activation of NK cells with an anti-FcγRIII antibody induces tyrosine phosphorylation of CD3ζ, and FcγRIII-associated CD3ζ might be downregulated in patients with cancer due to chronic inflammation (Eleftheriadis et al. 2008). CD3ζ is also associated with NKp46 and NKp30 receptors on NK cells, and its phosphorylation is required for transmission of activating signals upon antigen binding to these receptors. CD3ζ is also expressed in retinal ganglion cells and brain neurons, where it regulates neuronal development by reducing the size of the dendritic arbor. As a result, CD3ζ knock-out mice show an impaired learning behavior and memory due to altered NMDA and AMPA receptor signaling (Louveau et al. 2013).

Pathophysiological and Clinical Roles

Under normal circumstances, only the fully assembled TCR complex is displayed on the T-cell surface. Partially assembled TCRs are retained in the endoplasmic reticulum or targeted for degradation. However, certain pathologies might be associated with downregulation of CD3ζ. In these cases, despite the absence of CD3ζ, normal TCR numbers are expressed on the surface of T cells, for example, the tumor infiltrating T cells (Baniyash 2004). Downregulation of CD3ζ is also reported in autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis, and infectious diseases such as HIV and leprosy (Baniyash 2004). These reports have given rise to speculation over a role for downregulation of CD3ζ chain as an immune escape mechanism induced by various pathologies. Pregnancy is also associated with suppression of immunity, including downregulation of CD3ζ expression (Taylor et al. 2002). There are several mutations identified in the human CD3ζ gene (listed in Table 1) that cause primary immunodeficiencies and systemic lupus erythematosus (SLE) due to protein truncation or reduced expression levels. In addition more and more single nucleotide polymorphisms (SNPs) in the CD3ζ gene are reported to be associated with SLE as well as systemic sclerosis and rheumatoid arthritis (Takeuchi and Suzuki 2013). The disease likelihood for some SNPs in the CD3ζ gene differs between populations. This is, for example, the case for SNP rs2056626 that is associated with systemic sclerosis in European but not in Han Chinese populations (Wang et al. 2014). In mouse, elimination of the CD3ζ gene from the genome results in a drastically reduced thymus due to the lack of T cells and T-cell precursors. These cells express low level of a TCRαβCD3εγεδ complex. The number of single positive cells detected in the thymus is very low, which could be because of a failure to transition from double positive to single positive cells. In contrast to the thymus, spleen and lymph nodes contain large numbers of TCR-CD3low T cells (Malissen et al. 1993). Also, the number of γδ intestinal intraepithelial T lymphocytes is not significantly affected by deletion of CD3ζ (Ohno et al. 1993). However, those mice develop an autoantibody independent multiorgan inflammation at an age of 7 months (Deng et al. 2013). These studies indicate that that CD3ζ is not absolutely essential for T-cell development but it is required for maintaining tolerance.
CD3ζ, Table 1

Immunological disorders associated with mutations in CD3ζ


Immunological disorder



Primary immnunodeficiency

Rieux-Laucat et al. (2006)

−76 T insertion in the promotor


Nambiar et al. (2001)

344 bp insertion in 3′ UTR


Nambiar et al. (2001)

Splice mutation deleting of exon 7


Takeuchi et al. (1998)

Chimeric antigen receptors (CARs) used in cancer immunotherapy make use of the ITAM-containing and thus signaling-competent CD3ζ cytoplasmic domain (Dai et al. 2016). In these chimeric receptors an extracellular antibody single chain variable fragment (scFv) specific for a tumor-expressed antigen is coupled to the CD3ζ cytoplasmic domain by a transmembrane domain. These constructs are then expressed in T cells. Antigen binding to the scFv activates the CAR which leads to the phosphorylation of the CD3ζ cytoplasmic domain and subsequent activation of the T cell to kill the tumor cells.


CD3ζ is a type 1 TM protein and a subunit of the TCR and pre-TCR complexes. It forms a dimer and is necessary for assembly and expression of these receptors on the cell surface. The TCR exists in two different conformations, a resting state and an active state that is stabilized upon ligand-binding to the TCR. CD3ζ is part of this structural change. CD3ζ possesses three ITAMs with six tyrosines, which are phosphorylated only in the active conformation. Once phosphorylated, these tyrosines recruit SH2 domain–containing proteins for downstream signaling which ultimately leads to the development of pre-T cells in the thymus and activation of mature T cells in the periphery, which then initiate an immune response. CD3ζ is also part of several other receptors on T cells and NK cells and is expressed and has a function in neurons. Downregulation of CD3ζ has been noticed in patients with tumors and autoimmune and infectious diseases. Lastly, the cytosolic signaling tail of CD3ζ is employed in chimeric antigen receptors to be used in immunotherapy against tumors.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Anna Morath
    • 1
    • 2
    • 3
    • 4
  • Sumit Deswal
    • 1
    • 5
    • 6
  • Wolfgang W. A. Schamel
    • 1
    • 2
    • 3
  1. 1.Department of Immunology, Institute for Biology IIIUniversity of FreiburgFreiburgGermany
  2. 2.Centre for Biological Signaling Studies (BIOSS)University of FreiburgFreiburgGermany
  3. 3.Centre of Chronic Immunodeficiency (CCI)University Medical Center Freiburg and University of FreiburgFreiburgGermany
  4. 4.Spemann Graduate School of Biology and MedicineUniversity of FreiburgFreiburgGermany
  5. 5.Max Planck Institute of ImmunobiologyFreiburgGermany
  6. 6.Research Institute of Molecular PathologyViennaAustria