CD6 - CD6 molecule |Elisa - Clia - Antibody - Protein

Background

CD6 is a type I transmembrane glycoprotein expressed on the surface of T cells, some B cells, and a subset of natural killer (NK) cells. It plays a critical role in the modulation of immune responses, particularly in T-cell activation, differentiation, and immune synapse formation. CD6 is involved in regulating the threshold of T-cell receptor (TCR) signaling and acts as a co-stimulatory receptor that modulates immune responses.

CD6 is expressed in the thymus, where it is involved in T-cell development, including positive and negative selection during thymic maturation. In peripheral tissues, CD6 helps facilitate immune responses against pathogens, while maintaining immune tolerance to self-antigens. Dysregulation of CD6 signaling is implicated in a range of immune-related conditions, including autoimmune diseases, inflammatory disorders, and certain types of cancer.

CD6 is also known for its interaction with its ligand, Activated Leukocyte Cell Adhesion Molecule (ALCAM), which is present on antigen-presenting cells (APCs) such as dendritic cells, B cells, and epithelial cells. The CD6-ALCAM interaction is vital for T-cell-APC adhesion, facilitating the formation of the immune synapse, a specialized structure through which T cells communicate with APCs to receive signals required for activation and function.

Protein Structure

The CD6 protein consists of 668 amino acids and has a molecular weight of approximately 105 kDa. It is a type I transmembrane glycoprotein, meaning it has a single-pass transmembrane domain, with its N-terminal region located extracellularly and its C-terminal region residing intracellularly.

Primary Structure

The CD6 protein is composed of the following key domains:

• Extracellular Domain: This domain comprises three scavenger receptor cysteine-rich (SRCR) domains, which are highly conserved across species. These domains are responsible for interactions with ligands, such as ALCAM. The SRCR domains contain multiple cysteine residues that form disulfide bonds, stabilizing the domain structure. These domains are involved in mediating CD6's interaction with other proteins, notably ALCAM, which is critical for T-cell-APC adhesion and immune synapse formation.
• Each SRCR domain contributes to the structural integrity of CD6 and is believed to support multiple ligand-binding interactions, making CD6 versatile in immune signaling.
• Transmembrane Domain: CD6 contains a single hydrophobic transmembrane domain, which anchors the protein to the plasma membrane. This domain facilitates the localization of CD6 on the cell surface, allowing it to interact with its ligands and other membrane-bound proteins.
• Cytoplasmic Domain: The intracellular region of CD6 is relatively long and contains multiple phosphorylation sites, including tyrosine and serine/threonine residues, which play critical roles in signal transduction. Upon ligand binding and subsequent TCR activation, these phosphorylation sites become activated, recruiting intracellular signaling proteins such as SHP-1 (Src homology region 2 domain-containing phosphatase 1) and SHP-2, as well as syk and zeta-chain-associated protein kinase 70 (ZAP-70). These molecules regulate downstream signaling pathways that modulate T-cell responses, including cytokine production and proliferation.

Tertiary and Quaternary Structure

CD6 exists primarily as a monomer on the surface of T cells, although it may oligomerize or form larger complexes under specific conditions. CD6's interactions with other molecules, including the TCR-CD3 complex, co-stimulatory receptors, and its ligand ALCAM, are crucial for immune synapse formation. The binding of ALCAM to the extracellular SRCR domains of CD6 strengthens the interaction between T cells and APCs, facilitating more robust TCR signaling.

Classification and Subtypes

CD6 belongs to the scavenger receptor cysteine-rich (SRCR) superfamily, a large group of proteins characterized by the presence of SRCR domains. These domains are typically involved in binding various ligands, mediating immune signaling, and modulating receptor function. CD6 is closely related to other SRCR-containing proteins, such as CD5, which also regulates TCR signaling.

There are no known distinct subtypes of the CD6 molecule, but isoforms generated through alternative splicing have been identified. These isoforms may differ in the length of the cytoplasmic domain, which could influence their signaling potential and functional roles in different immune contexts.

Function and Biological Significance

CD6 is primarily involved in T-cell activation and immune synapse formation. Through its extracellular domain, CD6 interacts with ALCAM, facilitating T-cell adhesion to APCs. This interaction stabilizes the immune synapse, ensuring effective communication between the TCR and MHC-antigen complexes, thus promoting efficient antigen recognition and T-cell activation.

T-cell Activation and Co-stimulation

CD6 plays a significant role as a co-stimulatory molecule in T-cell activation. While the TCR provides the primary signal for T-cell activation upon recognition of an antigen-MHC complex, additional co-stimulatory signals are required for full activation. CD6, upon binding ALCAM, contributes to this secondary signaling pathway by amplifying TCR signals. This enhances T-cell proliferation, differentiation, and cytokine production, particularly in effector T cells such as Th1, Th2, and Th17 cells.

Immune Synapse Formation

The interaction between CD6 and ALCAM is crucial for the formation and stability of the immune synapse, a specialized structure that forms between T cells and APCs. This synapse allows for prolonged and stable interactions, facilitating effective T-cell activation and signal transduction. The immune synapse serves as a platform for the concentration of signaling molecules, enabling efficient communication between the TCR, CD6, and other co-stimulatory receptors.

Immune Regulation

CD6 also plays a role in immune regulation, particularly in modulating the threshold of TCR signaling. It can act as a fine-tuner, preventing overactivation of T cells and maintaining immune tolerance. This regulatory function is crucial in preventing autoimmune responses, where inappropriate activation of T cells against self-antigens can lead to tissue damage and chronic inflammation.

Clinical Issues

The dysregulation of CD6 expression or function is implicated in various autoimmune diseases, cancers, and inflammatory disorders.

Autoimmune Diseases

CD6 is associated with several autoimmune disorders, including multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis, and systemic lupus erythematosus (SLE). In these diseases, abnormal CD6 signaling or overexpression may lead to excessive T-cell activation and inflammatory responses. In MS, for example, CD6 expression is elevated in autoreactive T cells that attack the central nervous system, contributing to the neuroinflammation seen in the disease. Similarly, in RA, CD6+ T cells play a role in driving the inflammatory processes that lead to joint damage.

Cancer

CD6 expression is altered in various cancers, particularly T-cell lymphomas and leukemias. In some cases, CD6 acts as a marker for distinguishing between different types of hematologic malignancies. For example, CD6 expression is used to differentiate between chronic lymphocytic leukemia (CLL) and T-cell prolymphocytic leukemia (T-PLL). CD6 also plays a role in tumor immunity, where it can either promote or inhibit the immune response against cancer cells depending on the context.

Infectious Diseases

CD6 has been implicated in modulating immune responses during viral infections and chronic inflammation. In certain viral infections, such as HIV and hepatitis, CD6 expression on T cells may influence the course of the disease by modulating T-cell responses to infected cells.

Summary

The CD6 molecule is a critical regulator of T-cell activation, immune synapse formation, and immune tolerance. Structurally, it is a type I transmembrane glycoprotein with three SRCR domains, a transmembrane region, and a cytoplasmic tail rich in phosphorylation sites. CD6 primarily functions as a co-stimulatory receptor that interacts with ALCAM to modulate T-cell responses and facilitate T-cell-APC adhesion.

CD6 plays a key role in both the activation and regulation of immune responses, ensuring that T cells are effectively activated against pathogens while preventing overactivation that could lead to autoimmunity. Clinically, CD6 is implicated in autoimmune diseases, such as MS and RA, where abnormal CD6 signaling leads to chronic inflammation. In cancer, CD6 serves as both a diagnostic marker and a potential therapeutic target due to its role in tumor immunity. Understanding the structure and function of CD6 is essential for developing therapeutic strategies aimed at modulating immune responses in both autoimmune diseases and cancer.