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Modulating T Cell Responses by Targeting CD3
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15041189

The CD3-T cell receptor (TCR) is the canonical receptor complex on T cells. It provides the “first signal” that initiates T cell activation and determines the specificity of the immune response. The TCR confers the binding specificity whilst the CD3 subunits facilitate signal transduction necessary for T cell activation. While the mechanisms through which antigen sensing and signal transduction occur in the CD3–TCR complex are still under debate, revelations regarding the intricate 3D structure of the CD3–TCR complex might open the possibility of modulating its activity by designing targeted drugs and tools, including aptamers.

CD3 TCR T cell engager cancer immunotherapy

1. The T Cell Receptor: Intercepting Signals for T Cell Activation

1.1. Structure of the TCR/CD3 Complex

Incumbent to the function of T cells is the T cell antigen receptor complex or the TCR, a multimeric surface receptor that receives, integrates, and transduces the major histocompatibility complex (MHC)-restricted peptide antigen-based signals that are needed for activation of a T cell [1]. The TCR is made up of the α and β TCR chains that recognize the peptide–MHC complex. The CD3 signaling complex proteins are made up of δ-ε and γ-ε heterodimers that contain extracellular and intracellular domains, and a ζ- ζ homodimer that has a very short extracellular domain and a long intracellular domain. In an α-β T cell, the TCR is composed of a 1:1:1:1 ratio TCRαβ:CD3γε:CD3δε:CD3ζζ subunits [1][2][3].

1.1.1. TCR Chains

The highly variable TCR α β heterodimer ligates with cognate pMHC (Figure 1). It intercepts the antigenic signal of activation but cannot initiate T cell signaling by itself because of the short cytoplasmic tails of each of the two chains. These short tails are devoid of immunoreceptor tyrosine-based activation motifs (ITAMs) whose phosphorylation by Src family kinases such as LCK and FYN triggers T cell activation [4].
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Figure 1. TCR structure and T cell activation pathway. The TCRαβ recognizes the pMHC complex on the antigen-presenting cell at the immunological synapse. The transduction of the signal is mediated by the ITAM domains located in the CD3 intracellular domains, which are phosphorylated by Src family kinases. The signaling axis comprises numerous factors, such as Zap70 and Phospholipase C (PLC). The cascade ends up with the production of second messengers (Ca2+, diacylglycerol (DAG), and IP3) and the activation of Ras. These mediators lead to the upregulation of gene transcription by NF-κB, AP-1, and NFAT, triggering the activation of the T cell.
TCR α and TCR β chains are glycoproteins consisting of two immunoglobulin domains each and are linked covalently by a disulfide bond. The evolutionary conserved acidic, negatively charged, amino acid residues in their transmembrane domains form ionic interactions with basic (positively charged) residues located in the transmembrane domains of the CD3 subunits [1][2]. The α chain shares homology with the light chain of an antibody, and the β chain with the heavy chain [5]. Each subunit consists of a constant region (proximal to the membrane) and a variable region (distal to the membrane) [1][5]. TCR α and TCR β genes are randomly assembled from highly diverse V, D (only TCRβ), and J gene segments and the constant gene segment via a RAG1/2 recombinases-dependent process.
The V regions of each of the chains encode two of the three complementarity-determining regions (CDRs), whereas the third and most variable CDR is formed by random joining of the V (D) and J segments, with removal and nontemplated addition of nucleotides increasing diversity even further, thereby allowing for diverse antigen recognition by TCRs [6]. These hypervariable CDR loops bind to the MHC complexes presenting processed antigenic peptides (usually an 8 to 10 for MHC class I molecules and peptides of up to 20 aa for MHC class II molecules), and provide each TCR with its unique specificity, making each T cell different from its counterpart [6]. Thus, the immune system assembles a large, formidable army consisting of millions of T cells, each with a unique TCR, capable of recognizing and responding to millions of antigens specific to a wide range of pathogens as well as neoplastic tumor antigens [7][8]. 

1.1.2. CD3 Subunits

The relay of signals received by the TCR chains into the cytoplasm is essential for T cell activation. As the TCR α and β chains lack known intracellular signaling motifs, the transduction of activation signals to second messengers and intracellular transcription factors is coordinated by the intracellular signaling competent partners of the TCR: the CD3 protein complex (Figure 1) [1].
CD3 is a multimeric protein complex comprising three different subunits: CD3δε, CD3γε, and CD3ζζ dimers. Homologous CD3δε and CD3γε are heterodimers with single extracellular immunoglobulin domains that interact with the TCR α and β chains and have relatively short intracellular signaling domains. CD3γε and CD3δε dimers are similar to the CD79αβ subunits of the B cell receptor (BCR), which serve as auxiliary signaling components of the BCR [9].
The ζζ homodimer has a negligibly short ectodomain but an elaborate cytoplasmic domain that is essential for T cell signaling and activation. Unlike the TCR α and β chains that are highly diverse and vary among T cells, the CD3 subunits are invariant elements, shared among all α-β T Cells [10].
Each TCR contains two ε chains, one in each of the heterodimeric CD3δε and CD3γε subunits (Figure 1). The CD3ε chaperones the assembly and folding of all other CD3 subunit proteins, and thus, is essential for CD3/TCR expression [11][12][13]. Furthermore, CD3ε has a pivotal role in T cell activation, since it contains a cryptic proline rich sequence that is exposed on the cytoplasmic tail of the ε chain [14][15][16][17][18]. This conformational change has been shown to be necessary for further downstream signaling leading to T cell activation. This sequence has also been suggested to also play a role in amplifying T cell responses of low affinity T cell cognates [19]. It has also been implicated in initiating the recruitment of LCK that drives the ITAM phosphorylation cascade [20][21].
The δ and γ chains are highly homologous and perhaps arose from gene duplication [22]. Both γ and δ chains pair with ε chains, whose sequence is more conserved [6]. Some studies show that the γ and δ chains compete for binding with the ε chain and their homology allows them to pair interchangeably with the TCR chains for assembly [23]. Nevertheless, it is possible that δ and γ CD3 chains play slightly different roles in how they interact with the various subunits of the TCR and perhaps even in how they transmit T cell activation signals [3].
Transmembrane regions of all the CD3 subunits and TCR chains are in close association with each other through complementary electrostatic interactions between oppositely charged amino acid residues [2] (Figure 1). The TCR α associates with the heterodimeric CD3 δ-ε subunit whilst the TCR β chain associates with the CD3 γ-ε chains [2][24]. The ζ-ζ homodimer associates with the TCR α chain. Each of the CD3 subunits has acidic residues that are complementary and opposite in charge to the basic residues found in TCR α and β chains. This complementary electrostatic organization keeps the transmembrane coils of each of the TCR/CD3 subunits enrobed into each other, tethering the TCR/CD3 complex firmly into the cell membrane, and allowing it to move within the lipid bilayer as a single, independent functional unit [1][4] (Figure 1).
In α-β T cells, all the subunits of the TCR/CD3 complex are necessary and required for detection of the TCR complex on the cell surface by antibodies [25]. Several studies have shown that mutations or absence of even one of the CD3 proteins or TCR chains leads to levels of cell surface expression that are not detectable by conventional antibodies [26]. CD3/TCR subunits that are unable to pair with their complementary subunits might get retained in the ER, while incompletely assembled CD3/TCR pseudocomplexes stay sequestered in the ER and are translocated to the cytoplasm where they are targeted for lysosomal degradation [27]. The requirements for TCR expression were also confirmed by several transfection-based studies that tried to reconstitute an artificial TCR/CD3 complex in a mock T cell system in vitro. CD3 and TCR chains were introduced in varying permutations into host COS cells, but surface expression of the native conformation of the CD3/TCR complex was detected only when all of the four subunits were present in the cell [28][29]. This was also demonstrated in dog-pancreas-microsome-based mock T cell assemblies [28].
The ε chain and ζ chains are especially important in chaperoning and instructing the assembly and folding of the CD3 protein complexes [30]. CD3ε seems to have a dominant negative effect for TCR/CD3 expression, most likely because it pairs with both γ and δ chains to form CD3γ-ε and CD3δ-ε, whose expressions are necessary for TCR expression and thymocyte development. Their presence is required for the proper folding of the rest of the CD3 subunits [13]. CD3ɛ−/− mice show complete lack of mature thymocytes and not just a reduced number of T cells as in the case of γ, δ, or ζ deficiency. This effect can be rescued by the reintroduction of the CD3ε transgene. The ζ chain is important for the last stage of assembly. It is the last component that joins the assembly line and is involved in confirming the quaternary structure and surface expression of the TCR [12]. A ζ deficient T cell line fails to express TCR/CD3 on its surface, but the reintroduction of the ζ transgene rescues TCR expression [31].

1.2. Signaling Motifs in the CD3 Chains Protein Complex

Another primary and essential function of the CD3 complex involves signal transduction via their cytoplasmic tails which contain ITAMs. ITAMs consist of highly conserved consensus amino acidic sequences arranged in the following motifs: YXXL/I X6-8 YXXL/I [4]. Tyrosine residues located in ITAMs are preferentially phosphorylated by Src protein tyrosine kinase family members such as LCK and FYN and serve as docking sites for other tyrosine kinases such as ZAP70 that continue the signaling cascade [3]. This pathway eventually leads to the production of second messengers (Ca2+ and IP3) and Ras activation, which induces the activation of transcription factors such as NF-κB, NFAT, and AP-1, the characteristic signature of an activated T cell (Figure 1).
The γ, ε, and δ chains have one ITAM each, whilst the ζ chain has three ITAMs. As a result, each α-β T cell has a total of 10 ITAMs per TCR, 2 each on the CD3δ-ε and CD3γ-ε subunits, and 6 shared between the two ζ chains [32] (Figure 1). What is the purpose of having so many ITAMs in a single TCR? Two models have been proposed to explain this: “redundancy of signaling” and “differential signaling” [33][34]. The redundancy of signaling model suggests that engagement of all ITAMs is not required for T cell activation [33]. Activation of a T cell is determined by engagement of a specific, yet unknown, number of ITAMs (but not all 10 ITAMs) found distributed across all the CD3 subunits. Thus, ITAMs are present in excess numbers to safeguard against the nonactivation of T cells in case the threshold engagement needed for T cell activation is not reached. The differential signaling model proposes that ITAMs in CD3-γ, -δ, -ε, and -ζ chains have distinct functions and control differential activation, proliferation, and effector functions. This model allows for the description of CD3 signaling as a tunable, customizable, and versatile paradigm, where the desired T cell function can be executed by targeting desired ITAMs.

1.3. TCR Triggering

The process in which the TCR/CD3 proteins work together to receive, interpret, and initiate the process of T cell activation is known as T cell triggering [3]. It involves mechanical reception of cognate antigen by the extracellular TCR and subsequent intracellular changes in the CD3 complex and is a prerequisite for T cell activation and the generation of T cell mediated adaptive immunity [3]. The TCR’s organization as an oligomeric, multi-subunit protein complex makes its triggering and sustained signaling a very precise and fine-tuned process that is spatially, temporally, and mechanically regulated and modulated [3][35][36][37][38][39][40][41]. Triggering the TCR is not just dependent on mere interaction of agonistic pMHC or ligand with the TCR, but it is also incumbent upon how, when, and in what context the presentation of the stimulus takes place.
TCR triggering eventually leads to ITAM phosphorylation, recruitment of ZAP-70, LAT and consequent calcium flux, and downstream activation of transcription factors such as NF-κβ, NFAT, and AP-1 that is characteristic of an activated T cell [42]. Ligand binding seems to induce a conformational change in the cytoplasmic domains of the TCR/CD3 complex that induces release of the cytoplasmic tails of the CD3ε and ζ sequestered by ligation of its basic rich sequences (BRS) to acidic lipids and cholesterol present in the inner leaflet of the plasma membrane [35][41]. Upon release from the plasma membrane, CD3ε can expose its PRS, a proline rich sequence that ligates with the SH-3.1 domain of the NCK adaptor protein [41].

2. Strategies to Modulate T Cell Responses Targeting CD3

2.1. CD3 Agonistic Therapies to Rescue Function of T Cells

Several strategies have been developed over the years to rescue and boost T cell effector function in the immunotherapeutic treatment of cancerous diseases. Some strategies reinvigorate immunity indirectly by reprogramming the immunosuppressive elements in the tumor microenvironment (TME). Some targets aim to restore metabolic and nutrient balance [43]. HIF1-α inhibitors reduce hypoxia [44]; CD39, CD73, and adenosine receptor blockade prevents adenosine-mediated immunosuppression [45]; and glucose decoys such as 2-deoxyglucose (2-DG) [43] and glucose transport inhibitors [46] restore metabolic and nutrient availability for T cells by preventing excessive glycolysis in the TME.
One of the interventions that may rescue dysfunctional T cells in an immunosuppressive TME consists of providing T cell-activating stimuli in the form of TCR/CD3 agonists. The CD3 protein complex is the signaling subunit of the T cell, and thus, special attention has been paid to developing strategies that could rescue T cell function via targeting the axis where the first signal of T cell activation takes place through the CD3/TCR engagement. These interventions modify function and/or provide stimulatory signals directly to the T cells to rescue their activation potential, effector function, as well as memory formation ability.
The CD3 subunits are highly desirable targets for cancer immunotherapy due to several advantages that it may afford. The CD3 complex is a favorable target because of its nature as the signaling-machinery-orchestrating subunit of the T cell receptor. Its function, thus, makes it a target accessible for signal modulation and redirection. The CD3 subunits are the nonvariant subunits of the T cell receptor complex and are present on all T cells—both CD4+ and CD8+ T cells and α-β and γ-δ T cells—making them an easily accessible, pan-T cell, off the shelf, universal target. The multimeric nature of the CD3 complex—6 chains of 3 different types of CD3 proteins, 10 ITAMs of 6 different types as well as their modular arrangement as hetero and homodimers—provides a high degree of modularity and several foci of therapeutic intervention where the CD3 agonistic signal can be fine-tuned and customized to exhibit a wide range and scope of regulatory and modulatory effects on the T cell activation axis. Furthermore, targeting the CD3 subunits may provide the advantage of activating the T cell without depending on the context of MHC restriction. Still, not many drugs—immunotherapy or otherwise—have been developed targeting the CD3 subunits.

2.2. Anti-CD3 mAbs

In vitro studies performed in the 1980s using anti-CD3 mAbs showed that stimulating human T cells with the anti-CD3 antibodies can have distinctly different outcomes depending upon the mode of stimulation. When presented as immobilized on microbeads, anti-CD3 antibodies induced robust proliferation and activation of T cells, exhibiting a mitogenic effect. On the other hand, under proliferation-inducing conditions, if CD3 antibodies were cross-linked in solution, and presented in their soluble form to T cells, a weaker and even abortive signaling response was generated [47][48]. Thus, these complex T cell activation dynamics were the acting principles used in designing in vivo preclinical studies using the anti-CD3 antibodies that formed the stepping stones to developing the CD3 antibody-based clinical therapies used today.
With the development of the mouse anti-CD3 mAb 145-2C11 [49], the therapeutic potential and mechanism of action of CD3 murine agonist antibodies could be further tested in animal models. The use of mouse anti-CD3 mAb surprisingly exerts a potent effect in counteracting autoimmunity in vivo, despite its agonistic activity in vitro. The administration of the antibody in nonobese diabetic mice (NOD) over a period of 5 days induced antigen specific, long-lasting remission of the disease, without affecting the response against allografts. The treatment also prevented the generation of an immune response towards syngeneic pancreatic islet grafts, showing that tolerance can be induced by modulating CD3 activation [50].

2.3. The Importance of Providing CD3-Mediated Signaling In Situ: Bi-Specific T-Cell Engagers (BiTEs)

The agonistic potential of CD3 mAbs in the context of cancer immunotherapy could only be harnessed in the past few years, with the advent of bispecific antibody platforms [51][52]. Bispecific antibodies include many different types of constructs, with bispecific T cell engagers (BiTEs) as their most successful class [53]. BiTEs are made up of two scFvs—fusion proteins of the antigen-binding, variable domains of the heavy and light chains. BiTEs bring together two ScFvs—one specific for CD3, and the other for a tumor-associated antigen, fused together in a single bivalent construct [54][55][56][57]. BiTEs’ mechanism of action focuses on redirecting and guiding T cell effector function in an antitumor manner increasing the number of CD3 engagers in the tumor cell proximity. These synthetic bispecific mAbs simultaneously bind to T cells as well as tumor cells and redirect the cytolytic and effector activity of a primed and activated T cells towards targeting malignant cancer cells, thereby, potentiating the antitumor immune response [54][55][56][57].
BiTEs catalyze T cell activation only when they are tethered onto tumor cells using their tumor-binding arm due to the monovalency of the TCR binding arm and their soluble nature. Thus, they are able to precisely focalize their T cell activating power. Tumor cells coated with a certain density of BiTEs facilitate multivalent engagement of the TCR/CD3 complex and can promote activation of the T cell through TCR clusterization, bypassing the need of MHC-restricted activation of the T cell, and thus, representing a therapy that, in principle, is applicable in the same format to many patients. The optimized design of BiTEs renders the CD3 agonistic activity only in the tumor site, improving the antitumor efficacy and reducing the side effects of a systemic agonistic T cell activation [54][55][56][57].
ScFvs or single chain variable fragments are fusion proteins consisting of the heavy chain and the variable chain of the antigen binding arm of an antibody. CD3 ScFvs as well as ScFvs specific for several tumor-associated cell surface antigens such as CD19, CD20, CD33, B-cell maturation antigen (BCMA), CD123, and CD38, as well as for tumor antigens identified in hematological malignancies [51][54], have been generated for clinical application [51][54]. Using this arsenal, several bispecific BiTEs have been generated. Of particular interest is Blinatumomab, a CD19-directed CD3 T-cell engager [58][59] that was approved by the FDA in 2014 for the treatment of acute lymphocytic leukemia and consists of two scFvs, one engaging the CD3ε on the T cells, and the other engaging CD19 on B cells. Other BiTEs in clinical trials for the treatment of solid neoplasms target carcinoembryonic antigen (CEA) for nonsmall-cell lung carcinoma (NSCLC), Delta-like Ligand 3 (DLL3) for small cell lung cancer, epidermal growth factor receptor variant iii (EGFRviii) for glioblastoma, epithelial cell adhesion molecule (EpCAM) for NSCLC, human epidermal growth factor receptor 2 (HER-2) for breast cancer, Mucin 16 (MUC16) for ovarian cancer, prostate-specific membrane antigen (PSMA) for prostate cancers, and the somatostatin receptor (SSTR2) for neuroendocrine tumors, among others [52][54]. Thus, BiTEs provide off-the-shelf T cell agonism in a tumor-specific manner in vivo.

2.4. Aptamers as a Novel Class of CD3 Modulators

Aptamers are DNA- or RNA-based synthetic oligonucleotide drugs [60]. They are single-stranded species that adopt complex three-dimensional conformations that allow them to bind and interact with a wide variety of targets with high affinity and specificity. Hence, they behave like “chemical antibodies” with versatile applications and may be used to bind, block, activate, or modulate the activity of any chosen target [60].

Aptamers are selected through the systematic evolution of ligands using EXponential enrichment (SELEX), which is a structured process of pruning randomness [61][62]. During SELEX, a combinatorial library of millions and millions of unique oligonucleotide strands are sequentially and recursively exposed to the target of choice in iterative rounds of binding. These systematic binding screens organically and serendipitously select discrete, unique species—potential aptamer candidates—that are the best binders with robust affinity and exquisite specificity to the desired target.
Aptamer selection is not biased by the antigenicity of certain epitopes contained within the target protein, as happens in the case of selecting antibodies. Many monoclonal antibodies generated against the same protein might be favored to recognize similar overlapping immunodominant epitopes.

2.5. Targeting CD3 Complex with Small Molecules to Modulate T Cell Activation

One of the first-in-class TCR inhibitors was developed by the Alarcon group [63]. This molecule was designed via virtual screening and combinatorial chemistry. It was aimed to inhibit the interaction between the TCR/CD3 complex and the noncatalytic region of tyrosine kinase (NCK). TCR–pMHC binding induces a conformational change that exposes CD3ε cytoplasmic proline rich sequence (PRS) domains where NCK and LCK induce ITAM phosphorylation leading to T cell activation [64]. The blockade of NCK with the small molecule AX-024 modulates T cell activity by inhibiting ITAM phosphorylation and, thereby, preventing T cell activation. This drug is currently being explored for its use in autoinflammatory diseases such as psoriasis and asthma [63].
There are a few other candidate drugs that could be explored to improve CD3 signaling by modulating tyrosine phosphatase activity. LCK is an essential Src kinase that initiates the T cell phosphorylation of the CD3 ITAM, and its activity is tightly regulated by cycles of phosphorylation and dephosphorylation. Phosphorylation of LCK at Y505 keeps the kinase inactive while phosphorylation of Y394 is characteristic of an active kinase. CD45 is probably one of the main phosphatases involved in this process as it can eliminate the phosphate groups from both tyrosines with different efficacies, thus the CD45 expression levels conditions the extent of T cell activation [65]. Moderate expression of CD45 exerts a positive effect on T cell activation by eliminating the phosphate group from Y505.

3. Conclusions

The TCR/CD3 complex determines the specificity of the immune response and is the first signal needed to trigger T cell activation. The development of new approaches to modulate the activity of this complex is very attractive for immunotherapy. Most of the current studies are based on antibodies and chimeric bispecific proteins, but there are also other therapeutic platforms to be explored that could bring new advances in the field such as aptamers, oligonucleotide base ligands that can be used to target new modulatory epitopes in the TCR/CD3 complex, to generate new bispecific molecules, or as delivery agents to target other CD3 immunomodulatory drugs to T cells.

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Subjects: Immunology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Ashwathi Puravankara Menon
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Beatriz Moreno
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Daniel Meraviglia-Crivelli
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Francesca Nonatelli
,
Helena Villanueva
,
Martin Barainka
,
Angelina Zheleva
,
Hisse M. van Santen
,
Fernando Pastor
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Update Date: 15 Mar 2023
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