CD72 - CD72 molecule |Elisa - Clia - Antibody - Protein

Background

CD72 is a type II transmembrane glycoprotein belonging to the C-type lectin superfamily. It is mainly expressed on the surface of B cells, as well as some other immune cells such as dendritic cells. CD72 serves as a negative regulator of B cell receptor (BCR) signaling, modulating immune responses by attenuating excessive B cell activation and preventing autoimmunity.

CD72 interacts with protein tyrosine phosphatases, including SHP-1 and SHP-2, through its immunoreceptor tyrosine-based inhibitory motif (ITIM) in the cytoplasmic domain. When activated, CD72 negatively regulates BCR signaling, contributing to the maintenance of immune tolerance and B cell homeostasis. Given its central role in B cell regulation, CD72 is involved in autoimmune diseases, chronic inflammatory conditions, and lymphomas.

CD72 is also implicated in interactions with CD100 (Semaphorin 4D), a ligand that plays a key role in regulating immune responses. The interaction between CD72 and CD100 modulates B cell activation, T cell interactions, and dendritic cell function. This relationship is crucial for fine-tuning immune responses, ensuring that immune activation is balanced with immune regulation.

Protein Structure

CD72 is a type II transmembrane glycoprotein, which means it has a single transmembrane domain and an extracellular domain. Its protein structure can be described as follows:

Extracellular Domain:

• The extracellular region of CD72 contains a C-type lectin-like domain (CTLD). This domain is characteristic of proteins that participate in cell-cell interactions, and in CD72, it is crucial for binding to ligands such as CD100 (Semaphorin 4D). This interaction mediates important signaling pathways that influence B cell function.
• The extracellular domain also allows CD72 to engage in homophilic interactions (interacting with other CD72 molecules) or heterophilic interactions (interacting with different ligands), which are necessary for its regulatory functions in B cell signaling.

Transmembrane Domain:

• CD72 has a single-pass transmembrane helix that anchors the protein in the plasma membrane. This transmembrane region is important for its stability and the proper presentation of its extracellular domain on the cell surface.

Cytoplasmic Tail:

• The cytoplasmic domain of CD72 contains two ITIM motifs (Immunoreceptor Tyrosine-based Inhibitory Motifs). These motifs are responsible for recruiting and interacting with the protein tyrosine phosphatases SHP-1 and SHP-2. Upon activation of CD72, these phosphatases become phosphorylated and subsequently inhibit BCR signaling by dephosphorylating key signaling molecules.
• The cytoplasmic tail also regulates interactions with other intracellular proteins involved in modulating B cell activation thresholds, leading to either inhibitory or stimulatory effects, depending on the cellular context.

Glycosylation:

• CD72 is a glycosylated protein, and its glycosylation state is important for proper folding, stability, and function. Glycosylation also plays a role in ligand binding and cell surface localization.

Dimerization:

• CD72 is known to form dimers or higher-order oligomers on the cell surface, which is essential for its function in signaling. These interactions are key to its regulatory effects on B cells, particularly in fine-tuning the strength of BCR signaling.

Classification and Subtypes

CD72 is part of the C-type lectin superfamily, which includes proteins that participate in cell-cell adhesion, immune recognition, and signaling. Within this superfamily, CD72 is classified as a B cell co-receptor due to its involvement in modulating BCR signaling. Unlike other lectins that bind carbohydrates, CD72’s primary role is in protein-protein interactions, particularly with CD100.

CD72 does not have well-defined subtypes. However, it is encoded by the CD72 gene, which has four known allelic variants in humans. These variants, termed CD72a, CD72b, CD72c, and CD72d, show differences in their ability to regulate B cell signaling and autoimmunity susceptibility. These polymorphisms may influence the function of CD72 in specific populations or disease contexts.

Function and Biological Significance

CD72 plays a critical role in the regulation of B cell activation and is involved in various processes essential for immune homeostasis. Its major functions include:

Negative Regulation of BCR Signaling:

• CD72 is a negative regulator of B cell receptor (BCR) signaling. Upon BCR engagement with an antigen, CD72 is phosphorylated and recruits SHP-1 or SHP-2 to the intracellular domain, which dephosphorylates key components of the BCR signaling cascade. This reduces the strength of the B cell activation signal, ensuring that B cells are not over-activated, thus preventing autoimmunity.
• CD72-deficient mice display hyperactivation of B cells and develop autoimmune diseases, demonstrating its role as a checkpoint in B cell-mediated immune regulation.

Interaction with CD100 (Semaphorin 4D):

• CD72 functions as a receptor for CD100, which is expressed on both B cells and T cells. The interaction between CD72 and CD100 is essential for B cell survival, differentiation, and migration. Binding of CD100 to CD72 disrupts the association between CD72 and SHP-1, thereby promoting B cell activation by enhancing BCR signaling. This interaction highlights the dual regulatory role of CD72 in balancing immune tolerance and immune activation.
• In dendritic cells and T cells, CD72-CD100 interactions can also modulate the cross-talk between these immune cell types, influencing the overall immune response to infections and tumors.

Regulation of Germinal Center Formation:

• CD72 has been implicated in regulating the formation of germinal centers (GCs), which are sites in lymphoid tissues where B cells proliferate, undergo somatic hypermutation, and differentiate into memory B cells or plasma cells. Through its inhibitory role on BCR signaling, CD72 ensures that only high-affinity B cells survive and differentiate in the GC, preventing the selection of autoreactive B cells.

Role in Autoimmunity:

• The regulatory functions of CD72 are critical in preventing autoimmune diseases. Polymorphisms or dysregulation of CD72 expression have been linked to conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In these diseases, defects in CD72 signaling lead to hyperactive B cells and the production of autoantibodies, contributing to chronic inflammation and tissue damage.

Implications in Cancer:

• CD72 has been studied in the context of B cell lymphomas, where its expression can influence the growth and survival of malignant B cells. In certain types of B cell non-Hodgkin lymphomas, altered CD72 signaling may contribute to unchecked B cell proliferation and tumor development. CD72 has therefore emerged as a potential therapeutic target for modulating B cell activity in both autoimmune diseases and cancers.

Clinical Issues

Autoimmune Diseases:

• Given its central role in B cell regulation, aberrant CD72 function or expression is associated with autoimmune diseases. Systemic lupus erythematosus (SLE) is one of the conditions most strongly linked to CD72 dysfunction. In SLE, defects in the negative regulation of B cell activation by CD72 can lead to the production of autoreactive B cells and autoantibodies, which contribute to tissue damage and chronic inflammation.
• Additionally, polymorphisms in the CD72 gene are associated with susceptibility to autoimmune diseases. Certain CD72 variants may result in less efficient recruitment of SHP-1 or SHP-2, leading to impaired negative regulation of BCR signaling.

B Cell Lymphomas:

• CD72 has been implicated in the pathogenesis of B cell malignancies, including B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia (CLL). In these cancers, alterations in CD72 signaling may promote the survival and proliferation of malignant B cells. Targeting CD72 in these malignancies is being explored as a potential therapeutic strategy.

Therapeutic Targeting of CD72:

• Due to its regulatory role in B cell activation, CD72 is a potential target for therapeutic intervention in both autoimmune diseases and B cell lymphomas. Agents that modulate CD72 function, either by enhancing its inhibitory activity or by blocking its interaction with CD100, could be valuable in treating conditions associated with excessive B cell activation.

Summary

CD72 is a type II transmembrane glycoprotein primarily expressed on B cells and functions as a key regulator of B cell receptor signaling. Through its interactions with SHP-1, SHP-2, and CD100, CD72 acts as a negative regulator of B cell activation, promoting immune tolerance and preventing autoimmunity. Structurally, CD72 is characterized by an extracellular C-type lectin-like domain, a single-pass transmembrane region, and a cytoplasmic ITIM motif. Dysregulation of CD72 is associated with autoimmune diseases like systemic lupus erythematosus and certain B cell lymphomas, making it a potential therapeutic target in these conditions.