CD3 (including its subunits CD3ε, CD3δ, CD3γ, and CD3ζ) is the central component of the TCR-CD3 complex and is crucial for recognizing T cells and responding to antigens.
Every subunit of CD3 has distinct biological functions and multiple clinical applications. For example, CD3ε is critical for bispecific antibodies and immunotherapy, CD3δ shows promise in treating immune deficiencies, and CD3ζ plays a crucial role in CAR-T therapy.
An in-depth investigation into the roles and uses of CD3 subunits is expected to propel advancements in immunotherapy, providing new strategies for addressing cancer and immune system disorders.
Structure and signal transduction mechanism of TCR-CD3 complex
T cell receptors (TCRs) are primarily classified into TCRαβ and TCRγδ. In humans, TCRαβ is more prevalent and is known for its highly specific recognition of antigens presented by the Major Histocompatibility Complex (MHC).
However, the mature TCRαβ dimer lacks the signaling domains necessary for independently activating T cells. Consequently, it associates with CD3 molecules to form the TCR-CD3 complex, which enables signal transduction through their synergistic interactions.
The four subunits of the CD3 complex bind to TCRαβ in a specific stoichiometric ratio (TCRαβ: CD3γε: CD3δε: CD3ζζ = 1:1:1:1) to maintain the stability of the complex and to optimize the accuracy and efficiency of signal transmission.
Upon antigen stimulation, the intracellular domains of CD3 undergo conformational changes. Src family protein tyrosine kinases (PTKs) then phosphorylate the tyrosine residues within the immune receptor tyrosine activation motif (ITAM) of the TCR/CD3 complex.
This phosphorylation creates docking sites for proteins containing SH2 domains. Zeta-chain-associated protein kinase (ZAP-70) is recruited by these phosphorylated ITAMs and subsequently initiates downstream signaling pathways.
Biological functions of different subunits of CD3
Every subunit of CD3 has a distinct biological function and contributes to T cell development, activation, signal transduction, and immune regulation via synergistic interactions.
CD3ε serves as a crucial signaling center in the adaptive immune response. It plays a vital role in the TCR signaling pathway, influences the positive and negative selection of thymic T cells, regulates cell surface receptor signaling pathways, and promotes T cell differentiation and activation.
Beyond its immune functions, CD3ε is involved in cerebellar development and synaptic growth. It also regulates various signaling pathways, including the transmembrane receptor protein tyrosine kinase signaling pathway and the apoptosis signaling pathway, significantly impacting gene expression and apoptosis processes.
CD3γ is essential for establishing and maintaining cell polarity, assembling and transporting intracellular proteins, and contributing to lymphocyte apoptosis. While CD3δ shares functional overlap with CD3ε and CD3γ in co-regulating TCR signaling, its unique biological functions warrant further investigation.
CD3ζ plays a pivotal role in T cell activation, enhances IL-2 production, positively regulates protein localization, and is involved in T cell antiviral defense.
Clinical applications of different subunits of CD3
The critical function of CD3ε in T cell activation has made the use of bispecific antibodies that target CD3ε and tumor-associated antigens (TAA) for anti-tumor therapy a significant research area.
These bispecific antibodies reduce the distance between tumor cells and effector T cells and practically kill tumor cells. For example, Amgen's Blinatumomab is a bispecific antibody that targets CD3ε and CD19 and is used against B-cell acute lymphoblastic leukemia (B-ALL).
The drug works by binding to CD3ε on T cells and CD19 on tumor cells at the same time, thus redirecting T cells to the tumor cells and initiating T-cell-mediated cytotoxicity.
CD3ε is often used to develop immunotherapy drugs. For instance, humanized mouse models built using CD3ε can imitate the activation of T cells in humans, improving the assessment of the efficacy and safety of drugs that target CD3ε.
CD3ε can also work as a target for the screening and optimization of drugs, improving researchers’ ability to identify immunotherapy drugs with higher efficacy and lower toxicity.
It is important to note that further investigation is required of the binding epitope and CD3ε binding conformation of CD3ε-targeting bispecific antibodies, as the known bispecific antibodies have different binding characteristics for CD3 molecules.
Although clinical applications for CD3δ as a single target have not been as popular as the CD3 complex or the combination of CD3 with other targets, new research has pointed towards the important role of CD3δ in CD3δ-severe combined immune deficiency (CD3δ-SCID).
This condition is triggered by a single-base mutation in the CD3δ gene, resulting in premature termination of the CD3δ protein translation.
The CD3δ protein is crucial for blood stem cells to develop into T cells. Its loss or abnormal function has a severe impact on the production and function of T cells, and drastically reduces patient immunity, making them vulnerable to life-threatening conditions.
Researchers are currently investigating approaches to correct mutations in the CD3δ gene via gene editing techniques like CRISPR-Cas9 and base editing, with the goal of rehabilitating patients’ immune function.
Extensive research of CD3δ function and how it interacts with other CD3 subunits improves our current understanding of the molecular mechanisms underlying T cell development and immune regulation. This research also provides a theoretical foundation for the development of therapeutics for other immune-related conditions.
The clinical applications of CD3γ are primarily linked to its vital role in T cell activation and signal transduction. However, direct clinical uses of CD3γ are currently relatively rare. As research on T cell immune response mechanisms advances and new immunotherapies are developed, the clinical significance of CD3γ is expected to increase.
The intracellular domain of CD3ζ comprises of three ITAMs, which are key for TCR signaling. In CAR-T cells, the intracellular domain of CAR binds to CD3ζ, improving T cells' ability to identify and kill tumor cells.
FDA-approved CAR-T products like Tisagenlecleucel and Axicabtagene Ciloleucel use CD3ζ as a signal transduction domain to attain specific recognition and killing of tumor cells. This design has been used widely in CAR-T therapy and has resulted in outstanding clinical outcomes.
Conclusion
The TCR-CD3 complex is essential for T cells to recognize and respond to antigens. Each CD3 subunit contributes uniquely to T cell activation, signaling, and immune regulation and holds significant clinical relevance.
By deepening our understanding of the structure and function of the CD3 complex, we can develop more effective immunotherapy strategies, providing new hope for treating cancer and immune-related diseases.
Molecule list
Owing to their distinct physiological characteristics, CD3 molecules, and in particular, highly homogeneous heterodimers, are especially important. Choosing the correct product from Acro Biosystems’ wide range of CD3 molecules can help scientists meet their research needs for investigating CD3's biological functions and clinical applications.
- CD3E & CD3D
- CD3E & CD3G
- CD3 epsilon
- CD3 delta
- CD3 gamma
Image Credit: ACROBiosystems
References and further reading:
- Deng H, Niu Z, Zhang Z, et al. Back on the scene: Advances and challenges in CD3-related drugs in tumor therapy[J]. Drug Discovery Today, 2022, 27(8): 2199-2208. https://doi.org/10.1016/j.drudis.2022.04.019
- Lee K J, Chow V, Weissman A, et al. Clinical use of blinatumomab for B-cell acute lymphoblastic leukemia in adults[J]. Therapeutics and clinical risk management, 2016: 1301-1310. https://doi.org/10.2147/TCRM.S84261
- Kuhn C, Rezende R M, da Cunha A P, et al. Mucosal administration of CD3-specific monoclonal antibody inhibits diabetes in NOD mice and in a preclinical mouse model transgenic for the CD3 epsilon chain[J]. Journal of autoimmunity, 2017, 76: 115-122. https://doi.org/10.1016/j.jaut.2016.10.001
- McAuley G E, Yiu G, Chang P C, et al. Human T cell generation is restored in CD3δ severe combined immunodeficiency through adenine base editing[J]. Cell, 2023, 186(7): 1398-1416. e23. https://doi.org/10.1016/j.cell.2023.02.027
About ACROBiosystems
ACROBiosystems is a cornerstone enterprise of the pharmaceutical and biotechnology industries. Their mission is to help overcome challenges with innovative tools and solutions from discovery to the clinic. They supply life science tools designed to be used in discovery research and scalable to the clinical phase and beyond. By consistently adapting to new regulatory challenges and guidelines, ACROBiosystems delivers solutions, whether it comes through recombinant proteins, antibodies, assay kits, GMP-grade reagents, or custom services. ACROBiosystems empower scientists and engineers dedicated towards innovation to simplify and accelerate the development of new, better, and more affordable medicine.
Sponsored Content Policy: News-Medical.net publishes articles and related content that may be derived from sources where we have existing commercial relationships, provided such content adds value to the core editorial ethos of News-Medical.Net which is to educate and inform site visitors interested in medical research, science, medical devices and treatments.