ICAM3 - intercellular adhesion molecule 3 |Elisa - Clia - Antibody - Protein

Background

Intercellular Adhesion Molecule 3 (ICAM-3), also known as CD50, is a member of the immunoglobulin superfamily (IgSF) that plays a crucial role in cell-cell adhesion and immune system regulation. It is expressed predominantly on leukocytes, especially resting lymphocytes, and interacts with integrins to mediate various immune responses, including leukocyte trafficking, T-cell activation, and antigen recognition. ICAM-3 is particularly involved in the early stages of immune responses, functioning as a ligand for leukocyte function-associated antigen-1 (LFA-1), an integrin found on T cells and other leukocytes.

ICAM-3 acts as a facilitator of immunological synapse formation, helping leukocytes adhere to antigen-presenting cells and promoting signaling pathways critical for immune activation. Its interaction with integrins also promotes adhesion between leukocytes and endothelial cells, an important step in the migration of immune cells to sites of inflammation or infection. ICAM-3 is essential in regulating leukocyte dynamics and activation during immune surveillance and host defense.

The gene encoding ICAM-3, ICAM3, is located on chromosome 19p13.2 and is part of a family of adhesion molecules that includes ICAM-1, ICAM-2, and ICAM-5. While ICAM-1 is better characterized in inflammatory responses, ICAM-3 plays a significant role in immune cell communication under resting conditions and during the initiation of immune responses. Dysregulation of ICAM-3 has been linked to pathological conditions, including immune disorders and cancer.

Protein Structure

ICAM-3 is a type I transmembrane glycoprotein, consisting of five extracellular immunoglobulin-like domains, a single transmembrane domain, and a short cytoplasmic tail. Its structure is critical for its role in mediating cell-cell adhesion and interactions with integrins.

Extracellular Domain:

• The extracellular domain contains five Ig-like domains that are characteristic of members of the Ig superfamily. These domains are structurally important for ligand recognition and binding.
• The Ig-like domains are arranged in a linear fashion, and each domain consists of a sandwich of two β-sheets connected by a disulfide bond. This structure is common in adhesion molecules, allowing flexibility and enabling dynamic interactions with integrins such as LFA-1.
• ICAM-3 has a high affinity for LFA-1, specifically through its first two Ig-like domains. These domains contain specific amino acid residues that are involved in the binding process, facilitating strong adhesion between leukocytes and antigen-presenting cells.

Transmembrane Domain:

• The transmembrane domain of ICAM-3 consists of a single hydrophobic alpha helix, which anchors the protein to the plasma membrane. This domain plays a role in the stabilization of the molecule on the cell surface and in signal transduction processes.

Cytoplasmic Tail:

• The cytoplasmic tail of ICAM-3 is relatively short, but it is involved in intracellular signaling pathways. It interacts with various intracellular proteins, such as cytoskeletal components, to mediate changes in cell morphology and adhesion dynamics. While ICAM-3’s cytoplasmic domain does not have extensive signaling capabilities on its own, it participates in signaling cascades triggered by its extracellular domain through outside-in signaling mechanisms.

Classification and Subtypes

ICAM-3 belongs to the ICAM family, a subgroup of the immunoglobulin superfamily (IgSF), which also includes ICAM-1, ICAM-2, ICAM-4, and ICAM-5. Members of this family share structural features, such as immunoglobulin-like domains, and function primarily in cell adhesion and immune modulation.

• ICAM-1: Highly expressed during inflammation and involved in leukocyte extravasation.
• ICAM-2: Expressed on endothelial cells and involved in leukocyte transmigration.
• ICAM-3: Mainly expressed on resting leukocytes and involved in immune synapse formation.
• ICAM-4 and ICAM-5: Expressed in erythrocytes and neural tissues, respectively, with more specialized functions.

ICAM-3 is not divided into functional subtypes, but it shares functional similarities with other ICAM molecules, particularly ICAM-1, in mediating immune cell adhesion and signaling.

Function and Biological Significance

ICAM-3 plays a critical role in immune cell interactions, particularly in the early stages of immune responses. It serves as a ligand for LFA-1, an integrin expressed on T cells, B cells, neutrophils, and other immune cells. The ICAM-3/LFA-1 interaction is essential for immunological synapse formation, which facilitates T-cell activation and antigen presentation by allowing prolonged contact between T cells and antigen-presenting cells (APCs). This interaction enhances immune responses by stabilizing cell-cell contact and promoting the exchange of signaling molecules.

Immune Cell Adhesion:

• ICAM-3 is predominantly expressed on resting leukocytes and is involved in leukocyte-leukocyte adhesion during the early stages of immune activation. Its interaction with LFA-1 is crucial for the firm adhesion of immune cells to APCs, which is necessary for effective T-cell activation and immune synapse formation.

T-cell Activation:

• ICAM-3’s interaction with LFA-1 enhances T-cell receptor (TCR) signaling, leading to T-cell activation and the subsequent proliferation and differentiation of T cells into effector cells. This process is crucial for the immune system’s ability to respond to pathogens or foreign antigens.

Leukocyte Trafficking:

• In addition to its role in immune synapse formation, ICAM-3 contributes to leukocyte trafficking, particularly during immune surveillance. It aids in the adhesion of leukocytes to endothelial cells, facilitating their migration into tissues where they are needed for immune responses or inflammatory processes.

Signal Transduction:

• ICAM-3 can participate in outside-in signaling, where extracellular ligand binding (e.g., to LFA-1) triggers intracellular signaling pathways. This can lead to cytoskeletal rearrangements and changes in cell behavior, such as increased adhesion, migration, or immune activation.

Clinical Issues

Immune-related Diseases:

• Given its role in immune cell interactions, ICAM-3 is implicated in several immune-related diseases. Dysregulation of ICAM-3 expression or function can contribute to autoimmune disorders, where inappropriate activation of the immune system leads to tissue damage. Altered expression of ICAM-3 has been observed in conditions such as rheumatoid arthritis and multiple sclerosis, where aberrant immune cell activation contributes to chronic inflammation and tissue injury.

Infectious Diseases:

• Certain pathogens, such as HIV and Epstein-Barr virus (EBV), exploit ICAM-3 as a binding site to infect immune cells. HIV, for example, uses ICAM-3 as a co-receptor to enhance the infection of target cells. This makes ICAM-3 a potential therapeutic target in the context of viral infections, where blocking its interaction with pathogens could reduce viral entry and infection.

Cancer:

• ICAM-3 has also been implicated in cancer progression, particularly in hematological malignancies. Changes in the expression of ICAM-3 on leukemia and lymphoma cells can influence tumor cell interactions with the immune system. In some cancers, ICAM-3 expression may enhance tumor cell adhesion to the endothelium, facilitating metastasis. Conversely, reduced ICAM-3 expression can impair immune surveillance, allowing tumor cells to evade detection and destruction by the immune system.

Transplantation:

• In the context of organ transplantation, ICAM-3 may play a role in graft rejection. Interactions between ICAM-3 on immune cells and LFA-1 on T cells can contribute to the activation of immune cells that attack the transplanted organ. Therapeutic strategies that target ICAM-3 interactions could potentially reduce graft rejection and improve transplant outcomes.

Summary

ICAM-3 (CD50) is a crucial adhesion molecule that mediates interactions between immune cells, particularly during the early stages of immune responses. Its primary role is in immune synapse formation, where it binds to LFA-1 on T cells, promoting cell adhesion and T-cell activation. This interaction is essential for the immune system’s ability to mount effective responses to pathogens and other foreign antigens.

Structurally, ICAM-3 is a type I transmembrane glycoprotein with five immunoglobulin-like domains, a transmembrane region, and a short cytoplasmic tail. These features enable it to engage in strong interactions with LFA-1 and participate in signaling events that regulate immune cell behavior.

ICAM-3’s involvement in immune-related diseases, viral infections, cancer, and organ transplantation highlights its clinical significance. Dysregulation of its function can lead to pathological conditions, making ICAM-3 a potential target for therapeutic interventions aimed at modulating immune responses or preventing infection.