On the surface of immune cells like Natural Killer (NK) cells and a subset of T cells, the protein CD94 acts as a sensor. As a component of the body’s surveillance machinery, these cells patrol for signs of infection or cellular distress. Their actions are governed by a system of signals that dictate when to attack and when to stand down.
CD94 helps the immune system distinguish healthy cells from those that are cancerous or virally infected. This function is part of maintaining the balance between a protective immune response and preventing damage to the body’s own tissues. Understanding this receptor provides insight into how the immune system is regulated and can be manipulated to fight disease.
The CD94 Receptor Complex
The CD94 protein rarely functions in isolation, instead pairing with another protein to form a heterodimer. This partnership involves members of the NKG2 protein family. This requirement is fundamental, as CD94 provides a constant component of the receptor, while the NKG2 partner determines the message sent to the cell.
This pairing creates a C-type lectin-like receptor. The two most significant pairings are with the NKG2A and NKG2C proteins. Although NKG2A and NKG2C are structurally similar, subtle differences between them create opposing functions. The CD94/NKG2A and CD94/NKG2C complexes are the primary ways this system influences immune cell behavior.
The assembly of the CD94 and NKG2 proteins is an asymmetric pairing, creating a stable platform for interacting with its ligand, HLA-E. Structural studies show that the CD94 chain has a dominant role in binding to HLA-E. The variable NKG2 partner fine-tunes the interaction and dictates the subsequent signal.
Immune System Regulation
The CD94 receptor complex provides two opposing signals depending on its NKG2 partner. This determines whether the immune cell receives a “stop” or “go” message. This dual system is central to maintaining immune homeostasis by preventing attacks on healthy tissues while responding to threats.
The CD94/NKG2A complex is an inhibitory receptor. Healthy cells display HLA-E on their surface, which presents peptides from normal cellular proteins. When the CD94/NKG2A receptor on an NK cell encounters HLA-E, it sends an inhibitory signal into the NK cell. This signal is transmitted through Immunoreceptor Tyrosine-based Inhibitory Motifs (ITIMs) in the NKG2A protein, telling the NK cell to leave the healthy cell alone.
This inhibitory interaction has a higher binding strength than its activating counterpart, making the “stop” signal dominant. This hierarchy is a safety mechanism that keeps NK cells in a state of tolerance toward the body’s own cells. The system is designed to prevent autoimmunity.
In contrast, the CD94/NKG2C complex is an activating receptor that also recognizes HLA-E, though its binding is weaker. NKG2C associates with an adapter protein, DAP12, which contains an Immunoreceptor Tyrosine-based Activation Motif (ITAM). When this complex is engaged, it sends a “go” signal, prompting the NK cell to attack the target cell. This pathway allows the immune system to recognize cells whose HLA-E expression signals stress or infection.
Involvement in Viral Infections
The CD94 receptor’s role in combating viral infections demonstrates the adaptive nature of the immune system. Human cytomegalovirus (CMV), a common herpesvirus, is a compelling case study. In response to a CMV infection, the immune system’s NK cell population shifts to better control the virus.
CMV-infected individuals show a lasting expansion of NK cells carrying the activating CD94/NKG2C receptor. This suggests the receptor is involved in responding to CMV-infected cells. The virus can manipulate HLA-E expression, sometimes presenting a viral peptide that the CD94/NKG2C receptor recognizes, triggering an NK cell response.
This process forms “adaptive” or “memory” NK cells. These specialized NKG2C-positive cells are long-lived with heightened functions, ready to react if the virus reactivates. The presence of these cells in CMV-positive individuals shows how the innate immune system can be “educated” by a pathogen to create a tailored defense.
A Target in Cancer Immunotherapy
The inhibitory pathway that protects healthy cells can be exploited by cancer cells for immune evasion, a significant challenge in oncology. Many tumors increase HLA-E expression on their surface. This creates a shield that deactivates approaching immune cells.
When an immune cell with the inhibitory CD94/NKG2A receptor encounters a tumor cell with high HLA-E levels, it receives a “stop” signal. This engagement paralyzes the immune cell, allowing the tumor to grow. The presence of NKG2A on tumor-infiltrating lymphocytes is associated with poorer patient survival in several cancers, showing its role in suppressing anti-tumor immunity.
This mechanism makes the CD94/NKG2A-HLA-E axis a target for cancer treatments. Immunotherapy aims to block these inhibitory signals, “releasing the brakes” on the immune system. The therapeutic antibody monalizumab was developed for this purpose, binding to NKG2A to prevent its interaction with HLA-E on cancer cells.
By obstructing this connection, monalizumab restores the ability of immune cells to kill malignant cells. Clinical trials have explored its use, often combined with other immune checkpoint inhibitors to create a multi-pronged attack against tumors. This strategy is a promising approach to overcoming tumor resistance and unleashing the immune system’s potential against cancer.