CD3E - CD3 epsilon subunit of T-cell receptor complex |Elisa - Clia - Antibody - Protein

Background

CD3E (CD3 epsilon) is one of the key subunits of the T-cell receptor (TCR)-CD3 complex, which is vital for T-cell activation and immune responses. The TCR complex allows T lymphocytes to recognize and respond to antigens presented by major histocompatibility complex (MHC) molecules on antigen-presenting cells (APCs). CD3E plays a critical role in assembling the TCR-CD3 complex and facilitating signal transduction after antigen recognition.

The CD3E gene is located on chromosome 11q23 and encodes the CD3ε chain, a type I transmembrane protein essential for the assembly, expression, and signaling function of the TCR. Along with other CD3 subunits (CD3δ, CD3γ, and CD3ζ), CD3E forms part of the signal-transducing complex that transmits signals from the TCR upon antigen engagement. This signal initiates the cascade that leads to T-cell activation, differentiation, and proliferation, all of which are crucial for immune defense against pathogens.

In T-cell development, CD3E is indispensable for thymocyte maturation, where its role in the formation and surface expression of the TCR-CD3 complex ensures the proper selection of functional T cells that can recognize self-MHC but not self-antigens. Defects in CD3E can result in severe immunodeficiencies, autoimmunity, or dysfunctional T-cell responses. Given its essential function in immune surveillance, CD3E is also a target for therapeutic interventions in diseases such as autoimmune disorders, cancer, and infectious diseases.

Protein Structure

The CD3E protein is part of the CD3 complex, which also includes CD3D, CD3G, and CD3Z. These proteins associate with the TCRα/β or TCRγ/δ heterodimer to form the complete TCR-CD3 complex, responsible for antigen recognition and intracellular signal transmission.

Primary Structure:

• The CD3E protein is composed of 207 amino acids and has a molecular weight of approximately 23 kDa. It contains the following key structural domains:

1. Extracellular domain: The extracellular region is involved in interactions with other CD3 subunits (such as CD3D and CD3G) and contributes to stabilizing the TCR-CD3 complex at the cell surface. It is relatively short compared to the transmembrane and intracellular domains.
2. Transmembrane domain: The transmembrane segment anchors the protein to the plasma membrane of the T-cell. Like other CD3 subunits, CD3E contains a charged residue within the transmembrane domain that facilitates the formation of the TCR-CD3 complex through electrostatic interactions with the TCR chains.
3. Intracellular domain: The intracellular tail of CD3E is critical for signal transduction. It contains one immunoreceptor tyrosine-based activation motif (ITAM), a conserved signaling motif that becomes phosphorylated upon TCR engagement with an antigen-MHC complex. Phosphorylation of ITAMs recruits key signaling molecules, such as ZAP-70, which are necessary for the propagation of intracellular signaling events.

The ITAM is essential for initiating downstream signaling cascades, including activation of the MAPK, NF-κB, and calcium signaling pathways. These pathways are responsible for T-cell activation, proliferation, and the production of cytokines such as interleukin-2 (IL-2), which drives the immune response.

Quaternary Structure:

• CD3E functions as part of a heterodimer with CD3D or CD3G. These CD3E-CD3D and CD3E-CD3G heterodimers associate with the TCRα/β or TCRγ/δ heterodimer to form the TCR-CD3 complex. Additionally, two CD3ζ chains (CD3Z) are part of this complex, contributing to its signal transduction capacity. Each of these subunits contains ITAMs, which collectively ensure a robust and integrated signaling response upon antigen recognition.

The proper assembly and surface expression of the TCR-CD3 complex rely on CD3E’s interactions with both CD3D and CD3G subunits, as well as the TCR heterodimer.

Classification and Subtypes

CD3E is classified as part of the CD3 family of proteins, which also includes:

• CD3D (delta)
• CD3G (gamma)
• CD3Z (zeta)

These proteins work together to form the CD3 complex, which is required for the function of the TCR. CD3E does not have distinct subtypes but is critical in its interactions with the TCR and the other CD3 subunits.

The TCR-CD3 complex is broadly classified into two types based on the composition of the TCR heterodimer:

1. TCRαβ complex: Expressed on conventional αβ T cells, which recognize peptide antigens presented by MHC molecules.
2. TCRγδ complex: Expressed on γδ T cells, which have distinct antigen-recognition properties and are involved in recognizing non-peptide antigens.

In both types of TCR complexes, CD3E plays an essential role in signal transduction.

Function and Biological Significance

The primary function of CD3E is to participate in the assembly, surface expression, and signal transduction of the TCR-CD3 complex, which is essential for T-cell recognition of antigens and subsequent immune responses.

Key Functions:

Assembly and Surface Expression of the TCR-CD3 Complex:

• CD3E is crucial for the proper assembly of the TCR-CD3 complex in the endoplasmic reticulum and its transport to the cell surface. Without CD3E, the complex cannot be expressed on the T-cell surface, rendering the T cell incapable of antigen recognition.

Signal Transduction:

• Upon antigen recognition by the TCRα/β heterodimer, the ITAMs in the intracellular domain of CD3E become phosphorylated by the Src-family kinase Lck. This phosphorylation recruits ZAP-70, a kinase that activates multiple downstream signaling pathways that regulate T-cell activation, differentiation, and effector functions.

T-cell Development:

• In the thymus, CD3E is involved in the process of thymocyte selection. During positive selection, CD3E helps ensure that only T cells capable of recognizing self-MHC molecules, but not self-antigens, survive and mature into functional T cells. In the absence of CD3E, this selection process is impaired, leading to a failure in proper T-cell development.

T-cell Activation:

• Upon antigen recognition, CD3E plays an indispensable role in the activation of naive T cells, leading to their proliferation and differentiation into effector T cells. These effector cells are responsible for mounting immune responses to eliminate infected or cancerous cells.

Clinical Issues

Alterations in CD3E expression or mutations in the CD3E gene can lead to several immune-related clinical conditions.

Immunodeficiencies:

• Severe combined immunodeficiency (SCID): Mutations in CD3E can cause SCID, a condition characterized by the absence of functional T cells. Patients with SCID have a severely compromised immune system, rendering them susceptible to recurrent and life-threatening infections. CD3E deficiency leads to improper assembly of the TCR-CD3 complex, preventing T-cell development in the thymus and resulting in the absence of mature T cells in the periphery.

Autoimmune Diseases:

• Dysregulation of CD3E signaling has been implicated in several autoimmune disorders, such as systemic lupus erythematosus (SLE) and type 1 diabetes (T1D). In these conditions, abnormal T-cell activation can result in the immune system attacking self-tissues, leading to inflammation and tissue damage.

Cancer:

• The role of CD3E in T-cell activation has made it a target for immunotherapy in cancer treatment. Chimeric antigen receptor (CAR)-T cell therapy is an approach that involves engineering T cells to express receptors that specifically target cancer cells. CD3E signaling is often harnessed in these therapies to activate T cells against tumor cells. Additionally, CD3E-based therapeutics, such as anti-CD3 antibodies, are being investigated to modulate T-cell activity in various cancers.

Infectious Diseases:

• CD3E also plays a role in the immune response to infections. Defects in CD3E can result in an inadequate T-cell response to viral, bacterial, and parasitic infections, leading to chronic or recurrent infections.

Summary

CD3E, the epsilon subunit of the TCR-CD3 complex, is a fundamental protein in T-cell biology, responsible for the assembly, surface expression, and signal transduction of the TCR-CD3 complex. It plays an essential role in T-cell development in the thymus, and its phosphorylation following antigen recognition is critical for initiating T-cell activation. CD3E deficiencies can lead to severe immunodeficiencies such as SCID, while its dysregulation may contribute to autoimmune diseases. As a key player in immune responses, CD3E is also a target in cancer immunotherapy and other therapeutic applications aiming to modulate T-cell activity. Understanding the structural and functional properties of CD3E is critical for advancing our knowledge of immune regulation and developing new treatment strategies for immune-related disorders.