CD226, also known as DNAX accessory molecule-1 (DNAM-1), is a protein found on the surface of various immune cells, including natural killer (NK) cells and certain T cells. It belongs to the immunoglobulin superfamily, a group of proteins known for their roles in cell adhesion and signaling within the immune system. This protein functions as a receptor, helping immune cells detect and respond to target cells, initiating specific immune responses.
The Role of CD226 in the Immune System
CD226 functions as an activating receptor, primarily expressed on the surface of NK cells and CD8+ T cells. This receptor acts as a “go” switch, promoting the activation and cytotoxic functions of these immune cells. When activated, these cells become capable of recognizing and eliminating target cells.
CD226 interacts with specific binding partners, known as ligands, which are primarily CD155 (PVR) and CD112 (Nectin-2). This interaction can be thought of as a “lock and key” mechanism, where CD226 is the key that fits into the CD155 or CD112 lock on another cell. Upon binding, CD226 transmits signals to the immune cell, enhancing its ability to form stable connections with target cells and initiate their destruction. This process is important for maintaining immune surveillance and response.
CD226 in Cancer Immunology
The immune system continuously monitors the body for abnormal cells, a process termed immune surveillance, aiming to find and eliminate cancerous cells. CD226 plays a role in this defense mechanism by empowering NK cells and T cells to recognize and destroy tumors. When tumor cells express the CD226 ligands, CD155 and CD112, the CD226 receptor on immune cells can bind to them, triggering an anti-tumor immune response. This engagement leads to the release of cytotoxic granules like perforin and granzyme, which induce programmed cell death in tumor cells.
Despite this protective role, cancer cells have developed strategies to evade CD226-mediated immune recognition. One common mechanism involves reducing the expression of CD155 and CD112 ligands on their surface. This downregulation or shedding of ligands makes tumor cells less visible to the CD226 receptor, effectively cutting the “go” signal and allowing the cancer to grow unchecked.
Some tumor cells can also induce the degradation of CD226 on immune cells, impairing their function. For instance, CD155 on tumor cells can trigger CD226 degradation, which diminishes the effectiveness of CD8+ T cells. Additionally, certain cancers, like acute myeloid leukemia, can reduce CD226 expression on NK cells, weakening their cytotoxic activity. The presence of inhibitory receptors, such as TIGIT, CD96, and PVRIG, which compete with CD226 for binding to CD155 and CD112, can also contribute to immune evasion by attenuating the activating signals from CD226.
Involvement in Autoimmunity and Infections
An imbalance in the CD226 pathway can contribute to autoimmune diseases, where the immune system mistakenly attacks the body’s own healthy tissues. In conditions like rheumatoid arthritis and systemic lupus erythematosus, genetic variations in the CD226 gene have been linked to increased susceptibility. An overactive CD226 signal can lead to inappropriate immune cell activation against self-antigens, driving inflammation and tissue damage. For example, increased proportions of CD226+ B cells have been associated with heightened disease activity in systemic lupus erythematosus patients.
Conversely, CD226 also plays a beneficial role in fighting viral infections. Its activating function is important for NK cells to recognize and eliminate virus-infected cells, helping to clear the infection. For instance, CD226 is necessary for NK cells to identify cells infected with hepatitis C virus and human cytomegalovirus. In cases of severe influenza, certain CD226 genetic variants have been associated with disease severity, indicating its involvement in the immune response to viral pathogens.
Therapeutic Targeting of CD226
Immunotherapy harnesses the body’s own immune system to fight diseases like cancer and autoimmune disorders. Research into CD226 has opened avenues for new therapeutic strategies. These approaches aim to either boost or dampen the CD226 signal, depending on the disease.
For cancer treatment, scientists are exploring “agonistic” antibodies designed to activate the CD226 “go” button. These antibodies bind to CD226 and mimic the natural ligand interaction, thereby enhancing the immune system’s ability to attack tumors. This strategy aims to increase the cytotoxic activity of NK cells and CD8+ T cells, leading to more effective tumor cell killing. Such agonistic approaches are often investigated in combination with other immunotherapies, like PD-1 inhibitors, to achieve a stronger and more comprehensive anti-tumor effect.
For autoimmune diseases, the goal is to reduce the overactive immune response, so “antagonistic” antibodies are being developed. These antibodies are designed to block or dampen the CD226 signal, preventing immune cells from mistakenly attacking healthy tissues. By inhibiting the CD226/CD155 interaction, these antibodies can reduce T cell activation, proliferation, and the production of pro-inflammatory cytokines, which are characteristic of autoimmune conditions. This targeted modulation of CD226 signaling offers a potential pathway to restore immune balance in patients with autoimmune disorders.