CD247 - CD247 molecule |Elisa - Clia - Antibody - Protein

Background

CD247, also known as T-cell receptor zeta (TCRζ) or CD3ζ, is a critical component of the T-cell receptor (TCR) complex involved in T cell signaling. Encoded by the CD247 gene, this protein plays a pivotal role in the immune response by transmitting activation signals into T cells upon antigen recognition. CD247 is part of the CD3 complex (which includes CD3γ, CD3δ, CD3ε, and CD3ζ subunits) associated with the TCR on T cell surfaces. The CD3 complex facilitates TCR stability and signal transduction, making it essential for initiating the immune response to pathogens and malignant cells.

As a part of the immunological synapse, CD247 is expressed on T cells and natural killer (NK) cells, positioning it as an essential molecule for immune regulation and cellular communication. Its function is modulated through a variety of interactions, including phosphorylation and binding with other signaling molecules, making CD247 a key target in research focused on immunotherapy, autoimmunity, and infectious diseases.

Protein Structure

The structure of CD247 is crucial for its role in T cell activation. Its structure is characterized by three primary domains:

Extracellular Domain:

• The extracellular domain of CD247 is relatively small, consisting of only nine amino acids. This limited extracellular region contributes minimally to ligand binding but is involved in the stabilization of the TCR complex on the cell surface.

Transmembrane Domain:

• CD247 has a single transmembrane region that spans the lipid bilayer and anchors it to the cell membrane. This transmembrane domain enables CD247 to integrate into the TCR-CD3 complex. Notably, the transmembrane region contains a charged aspartic acid residue, which allows CD247 to interact closely with other charged residues in the transmembrane regions of other CD3 subunits (CD3ε, CD3γ, and CD3δ). This close association is crucial for TCR stability and signal initiation upon antigen binding.

Cytoplasmic Domain:

• The cytoplasmic tail of CD247 is the longest and functionally most significant portion, containing three immunoreceptor tyrosine-based activation motifs (ITAMs). These ITAMs are essential for signal transduction following TCR activation. Each ITAM contains a conserved sequence motif with tyrosine residues that can be phosphorylated by protein tyrosine kinases, including Lck and ZAP-70, in response to TCR engagement.
• Upon phosphorylation, these ITAMs act as docking sites for signaling molecules, particularly ZAP-70, which is crucial for the downstream signaling cascade that leads to T cell activation, proliferation, and differentiation. The phosphorylation of ITAMs in the CD247 cytoplasmic domain is therefore a critical event in T cell activation and immune response.

Classification and Subtypes

CD247 is classified as a component of the T-cell receptor (TCR) complex and is a member of the immunoglobulin superfamily. It belongs specifically to the CD3 complex family, which includes CD3γ, CD3δ, and CD3ε, each of which is vital for TCR function. CD247 itself does not have subtypes, but it can exist in different phosphorylated states, impacting its role in immune signaling.

In addition, CD247 is expressed not only on T cells but also on NK cells, where it contributes to their activation and cytotoxic functions. NK cells express CD247 as part of a complex with receptors like NKp30 and NKp46, which similarly rely on CD247 for initiating activation signals. This dual expression on both T cells and NK cells highlights the receptor’s versatile role in the immune system.

Function and Biological Significance

The primary function of CD247 is to serve as a signaling hub within the TCR complex. When a T cell encounters an antigen-presenting cell displaying a peptide bound to a major histocompatibility complex (MHC) molecule, the TCR recognizes this peptide-MHC complex, triggering the CD247 signaling pathway. Key functions of CD247 include:

Signal Transduction in T Cells:

• CD247 transmits activation signals upon TCR engagement through its ITAMs. The phosphorylation of these ITAMs recruits ZAP-70, which activates downstream pathways such as the MAPK, NF-κB, and NFAT pathways. These pathways are responsible for T cell activation, cytokine production, and the transcription of genes involved in immune response.
• This signaling cascade is essential for the development of effective immune responses, including T cell proliferation, differentiation into effector cells, and memory cell formation.

Role in NK Cell Function:

• In NK cells, CD247 participates in the signaling complexes of receptors like NKp30 and NKp46, facilitating cytotoxic responses against infected or malignant cells. Similar to its function in T cells, CD247 in NK cells helps propagate activating signals that lead to the release of cytotoxic granules and production of cytokines, which are crucial for innate immune responses.

Immunological Synapse Formation:

• CD247 plays a role in forming the immunological synapse, the contact point between T cells and antigen-presenting cells. The stability of the synapse and the subsequent signal transduction are essential for sustained T cell activation and immune response.

Regulation of T Cell Development:

• CD247 is crucial in T cell development in the thymus, where it facilitates the selection processes that ensure self-tolerance and the production of a functional T cell repertoire. Deficiency in CD247 can lead to impaired T cell maturation and reduced immune competency.

Clinical Issues

CD247 is involved in various clinical conditions due to its central role in immune signaling. Abnormal expression, mutations, or dysregulation of CD247 are associated with immune deficiencies, autoimmune disorders, and cancer:

Immunodeficiency:

• Deficiencies in CD247 expression or function can lead to immunodeficiency syndromes characterized by reduced T cell activation and impaired immune responses. CD247 deficiency can result in low surface expression of the TCR-CD3 complex, causing susceptibility to infections and impaired response to pathogens.

Autoimmune Diseases:

• CD247 dysregulation has been linked to autoimmune conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In these conditions, alterations in CD247 signaling pathways contribute to T cell hyperactivation and reduced immune tolerance, resulting in self-reactive immune responses.

Cancer:

• In cancers, especially hematological malignancies, altered CD247 expression has been observed in tumor-infiltrating lymphocytes (TILs). Reduced CD247 expression on TILs has been associated with T cell exhaustion, a state where T cells lose their effector functions and cannot effectively attack tumor cells. Restoring CD247 expression or function is being investigated as a strategy to reinvigorate TILs for improved cancer immunotherapy outcomes.

Infectious Diseases:

• Chronic infections, such as HIV and hepatitis C, are associated with downregulation of CD247, which contributes to T cell exhaustion. This downregulation impairs immune responses, allowing chronic pathogens to evade immune clearance. Therapies aimed at restoring CD247 expression or function could enhance immune responses in chronic infections.

Summary

CD247, or TCRζ, is an indispensable component of the TCR-CD3 complex on T cells, facilitating critical signaling pathways that initiate immune responses. Its structure, particularly the presence of three ITAMs in the cytoplasmic tail, enables it to act as a central signaling molecule. Through phosphorylation of these ITAMs and recruitment of signaling molecules, CD247 transduces signals that lead to T cell activation, proliferation, and differentiation. It is also involved in NK cell function, where it mediates cytotoxic responses against malignant or infected cells.

The dysregulation of CD247 is implicated in various immune-related conditions. In immunodeficiency syndromes, CD247 deficiencies result in impaired T cell responses and increased susceptibility to infections. In autoimmune diseases, abnormal CD247 signaling contributes to hyperactive immune responses against self-antigens. Additionally, in cancer and chronic infections, CD247 downregulation in T cells leads to T cell exhaustion, limiting immune responses against tumors and persistent pathogens.

Ongoing research is focused on understanding the molecular mechanisms governing CD247 function and targeting this receptor to develop therapies that restore or enhance immune responses in various diseases.