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_507


 CD3γ;  CD3δ;  CD3ε;  T3


CD3 is a complex of three type 1 transmembrane (TM) proteins expressed in T cells and most likely also in some neurons: CD3γ, CD3δ, and CD3ε.  CD3ζ ( CD247) is described in a separate chapter due to significant differences compared to CD3γ, CD3δ, and CD3ε. The CD3γ and CD3δ chains are glycoproteins, each of which forms a heterodimer with the nonglycosylated CD3ε chain. These chains associate with TCRαβ and a CD3ζζ dimer to form the αβ T cell antigen receptor (TCR) complex in αβ T cells (Figs. 1 and 2). The CD3 chains and CD3ζζ also associate with pTα and TCRβ to form the pre-TCR and with TCRγδ to form the γδTCR in the case of pre-T cells and γδ T cells, respectively. In murine but not human TCRγδs the CD3εδ heterodimer is replaced by a second CD3εγ heterodimer (Siegers et al. 2007). Each of the CD3 subunits possesses an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic tail, which becomes phosphorylated upon antigen binding to TCRαβ. Hence, the TCR is responsible for activation of a T cell upon antigen encounter and, thus, initiation of the immune response. In addition, CD3 and CD3ζ subunits bring TCRαβ to the cell surface. Within the immune system all three CD3 subunits are exclusively expressed on T cells; thus, they are used as T cell markers in clinical and basic research studies using flow cytometry.
CD3, Fig. 1

Schematic representation of the CD3 subunits. CD3ε, CD3γ, and CD3δ are shown with their structural features highlighted

CD3, Fig. 2

The TCR complex. CD3γ and CD3δ each form a heterodimer with CD3ε. These heterodimers associate with TCRαβ and CD3ζζ to generate the TCR complex that 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

In the late 1970s, monoclonal antibodies against T cells were generated. One such antibody, OKT3, was generated in 1979 by P. Kung and G. Goldstein (Kung et al. 1979). Later it was recognized that OKT3 binds to proteins involved in T cell activation and therefore the proteins were named T3. With the introduction of the immunological CD nomenclature in 1982, the proteins were renamed CD3. Now it is known that OKT3 binds to properly folded CD3ε expressed on the T cell surface, and the interaction has been characterized in detail using X-ray crystallography.

Genomic Organization and Protein Structure

The CD3 genes are clustered in a 50-kb region of chromosomes 11 and 9 in humans and mice, respectively (Tunnacliffe et al. 1988). CD3δ is located in the central position of the cluster and flanked on either side by the oppositely transcribed CD3γ and CD3ε gene loci. CD3γ is less than 2 kb apart from CD3δ, and CD3ε is located about 22 kb downstream of CD3δ. CD3δ is encoded by five exons, whereas seven exons encode CD3γ and seven or eight exons encode CD3ε depending on the presence of two and three miniexons in human and mouse, respectively (Fig. 3). Replacement of the promoter and the first two exons of CD3ε by a PGK-neor cassette in mice abolishes the expression of all three CD3 proteins (Wang et al. 1998). A model for the evolution of the CD3 gene family predicts that a single CD3 gene first duplicated to form CD3γ/δ and CD3ε and a second duplication of the CD3γ/δ gene subsequently generated the CD3γ and CD3δ genes as found in mammals (Gobel and Dangy 2000).
CD3, Fig. 3

Genomic organization of the human CD3 cluster. Approximate sizes of CD3 genes and the intervening sequences are shown

At protein level, the CD3γ, CD3δ, and CD3ε subunits share a similar structure, comprised of an extracellular immunoglobulin (Ig) domain, a stalk region, a TM region of 27 amino acids, and a cytoplasmic domain of 45–55 amino acids. The Ig domains of the CD3εγ and CD3εδ dimers have been characterized by X-ray crystallography and nuclear magnetic resonance (NMR). Like all proteins that enter the secretory pathway, the CD3 chains contain an N-terminal signal peptide that targets protein translation to the endoplasmic reticulum (ER). Since this peptide is cleaved cotranslationally, it is not present in the mature proteins.

The structure of these subunits can be described as follows.


The solution structure of the Ig domains of the mouse CD3εγ heterodimer showed that CD3ε and CD3γ both have C2-set Ig domains that interact with each other to form an unusual side-to-side dimer configuration. Crystal structures of the Ig domains of human CDεγ in combination with the OKT3 Fab fragment and human CD3εδ in combination with a single-chain fragment of the anti-CD3ε antibody UCHT1 have been solved (Arnett et al. 2004; Kjer-Nielsen et al. 2004). In contrast to mouse, human CD3ε contains a C1-set Ig fold. Human CD3γ has the C2-set Ig fold. Although the sequence identity between CD3ε and CD3γ is only 20%, the subunits share significant structural homology. CD3γ adopts different glycosylation patterns on naïve or stimulated T cells (Hayes et al. 2002). Human CD3δ contains a C1-set Ig fold (Fig. 4) and shows a differential glycosylation when incorporated in the αβTCR or the γδTCR (Siegers et al. 2007).
CD3, Fig. 4

Crystallographic structures of the immunoglobulin domains of CD3εγ and CD3εδ. Crystal structures were obtained from the protein data bank (human CD3γε heterodimer in complex with antibody OKT3 Fab fragment, PDB ID: 1SY6 and human CD3δε heterodimer in complex with UCHT1 single-chain antibody fragment, PDB ID, 1XIW) and figures generated using the software MacPymol. For simplicity, the antibody fragments are omitted

In addition, CD3ε possesses several negatively charged residues in the N-terminal region before the Ig domain, which can be cleaved by metalloproteases. This results in two CD3ε isoforms with different molecular weights and isoelectric points.

Stalk Region

CD3ε, CD3γ, and CD3δ molecules each contain a CXXC motif in their short stalk region connecting the Ig-like domains to their TM regions. Some reports have suggested that the CXXC motif is involved in the dimerization of CD3ε to CD3γ or to CD3δ, or in the binding of CD3 dimers to TCRαβ. However, other studies did not find significant impairment of assembly either of CD3 dimers or of the TCR complex by mutating those cysteines in CD3ε. Molecular dynamics studies have suggested that the β strands of CD3ε become more rigid upon anti-CD3 antibody binding. This stiffening effect can be transmitted to the stalk region. The CXXC motif seems to participate in the transmission of the stiffening effect to the TM and cytoplasmic parts. In accordance with this, mutation of these cysteines in CD3ε prevented both the transmission of an antigen-induced conformational change to the cytoplasmic tail of CD3ε (CD3 conformational change) and the activation of T cells (Martinez-Martin et al. 2009; Blanco et al. 2014). Thus, the stalk region might be important in transmitting the information that antigen has bound from TCRαβ to the cytoplasmic tails of CD3. This might be done using an allosteric mechanism (Swamy et al. 2016).

Transmembrane Region

CD3ε and CD3δ each possess an aspartic acid residue in its TM region, while CD3γ possesses a glutamic acid residue. These four acidic amino acids, along with two acidic residues of CD3ζζ dimer and three basic TM residues on TCRαβ (Fig. 1), play an important role in the assembly of TCRαβ with CD3εγ, CD3εδ, and CD3ζζ dimers. However, to date it is not known whether these TM residues are charged or not.

Cytoplasmic Region

In the cytoplasmic portion, the CD3 subunits possess the signaling motifs discussed below.

Immunoreceptor Tyrosine-Based Activation Motifs

ITAMs have a consensus sequence of Yxx(L/I)x 6–8Yxx(L/I) (Reth 1989). This motif occurs in a variety of proteins that include CD3ε, CD3δ, CD3γ,  CD3ζ (three ITAMs on each  CD3ζ chain), Ig-α, Ig-β, FcεR1β, FcεR1γ, DAP12, and some viral proteins, e.g., the LMP2A protein from the Epstein-Barr virus. The ITAM tyrosines of CD3 are necessary for ITAM signaling and, when both are phosphorylated, bind to the tandem Src homology 2 (SH2) domains of  ZAP70 or Syk. Each TCR complex contains 10 ITAMs. Whether the function of the large number of ITAMs is of qualitative or quantitative nature is still unclear Holst et al. (2008). Mice were generated in which all different combinations of ITAMs were mutated (the tyrosines to phenylalanines). It was concluded that it is mainly the ITAM number that matters Holst et al. (2008). Mutations in four to eight of the ten CD3 ITAMs developed a severe autoimmune disease due to a conversion of negative into positive selection signals of the T cells in the thymus. This demonstrates the importance of a high ITAM number to induce central tolerance. The nonconserved amino acid sequences within the ITAMs, particularly at positions Y + 1 and Y + 2, might facilitate the association of signaling proteins through SH2 domain-containing domains. Indeed, in addition to ZAP70, phosphorylated ITAMs bind to Syk, Fyn, Lck, p85, Shc,  SHIP, and other signaling proteins (Borroto et al. 2014a). However, the nonphosphorylated ITAMs of CD3 also act as docking site for proteins as it was reported for the small GTPase TC21, the microtubule end-binding protein EB1, and the GPCR-interacting protein β-arrestin1 (Delgado et al. 2009, Martín-Cófreces et al. 2012, Fernández-Arenas et al. 2014). These proteins play a role in maintaining cell viability, functioning of the immune synapse, and TCR internalization. The first tyrosine of the CD3ε ITAM lies within a proline-rich region. Phosphorylation of this tyrosine interferes with the binding of Nck (Paensuwan et al. 2016). CD3 proteins do not contain signaling relevant non-ITAM tyrosines.

Di-Leucine-Based Motif

The di-leucine-based motif (DxxxLL) of CD3γ binds to the clathrin-coated vesicle adaptor proteins AP-1 and AP-2 and is involved in downregulation of the TCR (Dietrich et al. 1994). Phosphorylation of serine 126 induces a conformational change in the context of complete TCR. The DxxxLL motif is then exposed for AP-1/2 binding, a mechanism required for downregulation. In an incompletely assembled TCR lacking  CD3ζ, the DxxxLL motif is directly accessible and recognized by AP-1 at the trans-Golgi network, leading to sorting of TCRαβCD3εγεδ to lysosomes for degradation. In contrast, in the fully assembled TCR complex, the DxxxLL motif is inaccessible, and the receptor follows the default transport route to the plasma membrane. Thus,  CD3ζ masks the CD3γ DxxxLL motif in the fully assembled TCR, and this effect relies more on the length of the cytoplasmic tail than on the primary sequence (Lauritsen et al. 2004).

Proline-Rich Sequence

Proline-rich sequences (PRS) bind to Src homology 3 (SH3) domains. In CD3ε, the evolutionarily conserved PRS (RPPPVPNPDYEP) binds to the first SH3 domain of the adaptor protein Nck upon the CD3 conformational change stabilized by antigen binding to the TCR (Gil et al. 2002). Inhibition of this interaction by knockout of the two Nck isoforms (Roy et al. 2010a, b), mutation of the PRS by substitution of the two central prolines with alanine (Borroto et al. 2013), or blockade of the CD3 conformational change by a cysteine 80 to glycine substitution in CD3ε (Blanco et al. 2014) impaired αβ T cell development in mice and activation of T cells. Thus, the recruitment of Nck to the PRS in CD3ε is necessary for full TCR signaling. Accordingly, TCR-induced signaling events were adversely affected in peripheral T cell of CD3ε PRS mutated mice (Borroto et al. 2014b). Interestingly, Nck can also use its SH2 domain to bind to phosphorylated ITAM tyrosines (Paensuwan et al. 2016). In contrast to the αβTCR, the γδTCR does not undergo the CD3 conformational change upon antigen binding (Dopfer et al. 2014, Blanco et al. 2014). In addition, Eps8L1 (epidermal growth factor receptor pathway substrate 8-related protein 1) binds to the CD3ε PRS (Kesti et al. 2007), but the functional consequence of this interaction has yet to be determined.

Basic Rich Stretch

The basic rich stretch (BRS, also called phospholipid binding motif) locates to the juxtamembrane portion of the CD3ε cytoplasmic tail (Deford-Watts et al. 2009). Positively charged residues of the BRS enable this part of CD3ε to bind to acidic phospholipids in vitro. It was suggested that the CD3ε cytoplasmic domain dissociates from the plasma membrane upon Ca2+ influx after TCR triggering (Shi et al. 2013). Thus, the influx of Ca2+ ions upon TCR signaling could lead to signal amplification. The BRS is also shown to be important for localization of CD3ε to the immunological synapse and binding to signaling proteins GRK2 (G protein-coupled receptor kinase2) and CAST (CD3ε-associated signal transducer).

Serine Residues

Unique to the cytoplasmic tail of CD3γ are three serine residues which represent potential phosphorylation sites that can subsequently interact with proteins containing phospho-serine binding domains such as 14-3-3, WW, and MH2 domains.

Retention Motif

All subunits of the TCR contain ER retention/retrieval motifs. These motifs are important for sequential assembly of the TCR components and assure that only a fully assembled TCR is expressed on the cell surface. Different subunits contain different numbers of retention motifs. The CD3ε retention motif (an elongated α-helix followed by βI’ turn and contains three closely spaced residues, tyrosine, leucine, and arginine) seems to be dominant as the CD3δε and CD3γε heterodimers reach the cell surface when the CD3ε retention motif is mutated. The CD3ε retention motif is overridden only when CD3ζ is incorporated in the TCR complex.

Assembly and Membrane Organization

Assembly in the ER begins with the formation of CD3εδ and CD3εγ heterodimers. CD3εδ then associates with TCRα using the potentially charged TM residues (see above). CD3εγ dimers associate with TCRβ in a similar manner (Alarcon et al. 1988). Once TCRαβCD3εγεδ has formed, the CD3ζζ homodimer is the last subunit to join. The CD3ζζ homodimer requires the aspartic acids at position six in the TM regions of CD3ζ for interaction with the arginine residue in TCRα, and upon its incorporation, the whole TCR complex is transported to the plasma membrane (Sancho et al. 1989). In addition, the ectodomains of CD3δ and CD3γ play a role in selective association of CD3εδ to TCRα and CD3εγ to TCRβ.

No structural data have been obtained for the entire TCR complex yet. However, mutagenesis studies suggest that CD3εγ and CD3εδ are located on the same side in the TCR, so that the other side can mediate homotypic TCRαβ interactions. Using electron microscopy and Blue Native-PAGE studies, it was shown that TCRs exist both as monovalent receptors with a stoichiometry of TCRαβCD3εγεδζζ (see below) and preclustered multimers of the monovalent receptor, called nanoclusters (Schamel et al. 2005; Schamel and Alarcón 2013). The degree of TCR nanoclustering increases with increasing concentrations of cholesterol (Molnár et al. 2012). TCR nanoclusters increase the avidity towards multimeric pMHC and thus signal outcome. Cholesterolsulfate reduces TCR nanoclustering and thus reduces ITAM phosphorylation and further downstream signaling upon TCR stimulation (Wang et al. 2016). It was shown that cholesterol binding to TCRβ keeps the TCR in the resting, inactive conformation (Swamy et al. 2016). Ligand binding shifts the equilibrium to the active conformation in which cholesterol is no longer associated to TCRβ.


Together with  CD3ζ, the CD3 subunits are the main signaling units in the TCR. Upon antigen binding to TCRαβ, a conformational change in CD3ε exposes the PRS where the adaptor protein Nck can bind as discussed earlier. Antigen binding also leads to the phosphorylation of the ITAM tyrosines by the Src family kinases Lck and Fyn, which results in association of  ZAP70 to phospho-tyrosines with its tandem SH2 domains.  ZAP70 phosphorylates the adaptor protein  LAT on several sites, which act as the hub for initiation of downstream signaling. The CD3 subunits also regulate surface TCRαβ expression. Knock-out mice and humans that lack individual CD3 chains show impairment in TCR expression. CD3δ associates with the coreceptor CD8 and couples the TCR to CD8 for signaling by the CD8-associated kinase Lck (Doucey et al. 2003) and for enhanced apparent affinity to peptide-MHC. As CD3 subunits are also associated with the pre-TCR on developing thymocytes, CD3-mediated signaling is required toward progression of the double-positive thymocytes and TCRα gene rearrangement. Pro-T cells express low levels of CD3 possibly in association with calnexin in the absence of TCRαβ at their surface. Anti-CD3ε antibody-induced cross-linking of the CD3 molecules on pro-T cells of RAG-1−/− mice in vivo induces differentiation of these pro-T cells into pre-T cells. This suggests that CD3 has a functional role in pro-T cells.

Various transfection studies, genetic knock-out mice, and natural mutations have revealed the importance of individual CD3 subunits in T cell development. In the absence of intact CD3ε, thymocytes do not progress beyond the CD44−/1ow CD25+ triple-negative stage in the CD3ε knock-out mouse. CD3γ is essential for development of both the αβ and γδ T cell lineages in mice, whereas human patients lacking CD3γ develop αβ and γδ T cells in which CD3γ is replaced by CD3δ. To study human immunodeficiency caused by a lack of CD3γ, a humanized mouse model was established that is both deficient for CD3γ and CD3δ but carries the gene for human CD3δ (Fernández-Malavé et al. 2006). CD3δ-deficient mice develop γδ T cells but no αβ T cells. Human patients lacking CD3δ, on the other hand, fail to develop either αβ or γδ T cells (Dadi et al. 2003). These observations can be explained by the distinct stoichiometries of human and mouse γδTCR. While the stoichiometry of human γδTCR is TCRγδCD3εγεδζζ, mouse γδTCR has a stoichiometry of TCRγδCD3εγεγζζ (Siegers et al. 2007). Interestingly, CD3γ+/− CD3δ+/− haplosufficient mice show a reduced TCR expression on γδ T cells which correlates with a decreased signaling strength (Muñoz-Ruiz et al. 2016). Accordingly, there might be a role for CD3δ in the intracellular assembly of the γδTCR. In contrast, αβ T cells were not affected in those mice. Also the individual CD3 subunits have partially different roles in T cell development at distinct stages of development. CD3ε-deficiency blocks the T cell development at a triple-negative stage whereas CD3δ is more important for positive selection as evident by the mice lacking CD3δ in which T cells progress from a CD4 CD8 double-negative to a CD4+ CD8+ double-positive stage but fail to undergo positive selection.

Pathophysiological and Clinical Roles

Absence of individual CD3 subunits causes immunodeficiencies of varying severity. As discussed earlier, CD3δ- and CD3ε-deficient humans fail to develop either αβ or γδ T cells, resulting in severe combined immunodeficiency (SCID) (Dadi et al. 2003; Soudais et al. 1993). Deficiency in CD3γ results in a milder form of SCID, since T cells are present in which CD3γ is replaced by CD3δ (Arnaiz-Villena et al. 1992). Table 1 summarizes the effect of the deficiencies in individual CD3 subunits in human and mouse. In addition, anti-CD3 antibodies are used in the clinic for treatment of various immunological disorders. In fact, OKT3 was the first monoclonal antibody to be approved by the US Food and Drug Administration (FDA) in 1986 for clinical use. OKT3 is an immunosuppressant given to reduce acute rejection in patients with organ transplants such as allogeneic renal, heart, and liver transplants. Anti-CD3 antibodies are also used for the treatment of T cell acute lymphoblastic leukemia. Immediately after administration of anti-CD3 antibodies, T cells are depleted from circulation. OKT3 appears to kill CD3 positive cells by inducing Fc-mediated apoptosis, antibody-mediated cytotoxicity, and complement-dependent cytotoxicity. In addition, removal of the TCR from the cell surface by internalization is thought to be a mechanism of action. Due to their mitogenic activity and release of cytokines, Fc receptor (FcR)-binding antibodies such as OKT3 induce flu-like symptoms in treated patients. Thus, in 1994 the first humanized non-FcR-binding antibodies specific for human CD3 were produced and by late 1990s successfully used in the clinic. Teplizumab and Visilizumab are some of the non-FcR-binding anti-CD3 antibodies used to date (Chatenoud and Bluestone 2007).
CD3, Table 1

Immunological disorders associated with different CD3-deficiencies in human and mouse



Presence of αβ T cells

Presence of γδ T cells






Mild immunodeficiency

Recio et al. (2007)



Dadi et al. (2003)



de Saint Basile et al. (2004)



Presence of αβ T cells

Presence of γδ T cells



Haks et al. (1998)



Dave et al. (1997)


Malissen et al. (1995)


The three CD3 subunits CD3γ, CD3δ, and CD3ε form an integral part of the TCR complex and, together with  CD3ζ, provide TCRαβ (and TCRγδ) with the signal transmission ability upon antigen binding. The CD3 proteins are type 1 TM proteins that form dimers, CD3εγ and CD3εδ, containing diverse cytoplasmic signaling motifs for inducible interaction with kinases, adaptor proteins, and other signaling proteins. The CD3 subunits can change their conformation using an allosteric mechanism, in which the active conformation is stabilized by ligand binding to the TCR. With its proline-rich sequence CD3ε plays an important role is this conformational switch. Thus, CD3 subunits are crucial for both normal T cell development and their function in the periphery. Lack of any of these subunits causes immunodeficiencies. Anti-CD3 antibodies are being used in the clinic as immunosuppressants to reduce acute transplant rejection and in the treatment of T cell acute lymphoblastic leukemia.


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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