NKG2A is a protein found on the surface of certain immune cells, particularly natural killer (NK) cells and a subset of T cells. These immune cells recognize and eliminate abnormal cells, such as those infected with viruses or cancerous cells. NKG2A acts as an “off switch,” helping regulate the balance between immune activation and preventing attacks on healthy tissues.
How NKG2A Regulates Immune Responses
NKG2A functions as an inhibitory receptor, sending signals that dampen immune cell activity. It does this by forming a complex with another protein called CD94. This CD94/NKG2A complex recognizes and binds to human leukocyte antigen-E (HLA-E), present on the surface of many healthy cells. This interaction allows immune cells to distinguish healthy cells from those that might be infected or cancerous.
When NKG2A binds to HLA-E, it triggers a signal inside the immune cell. This signal is mediated by regions within the NKG2A protein called immunoreceptor tyrosine-based inhibition motifs (ITIMs). Upon binding, ITIMs become chemically modified, recruiting proteins that block the immune cell’s ability to attack. This puts the “brakes” on the immune response, preventing NK cells or T cells from mistakenly destroying healthy cells and minimizing damage to the body’s own tissues.
NKG2A’s Influence on Disease
The inhibitory role of NKG2A can be exploited by various diseases, allowing them to evade detection and destruction by the immune system. Cancer cells, for instance, often increase HLA-E production on their surface. By overexpressing HLA-E, these cancer cells engage the NKG2A receptor on NK cells and T cells, effectively “hiding” from immune surveillance. This allows cancer cells to grow and spread without being eliminated.
Cells infected with viruses can also upregulate HLA-E to avoid immune recognition. This strategy allows viruses to persist by tricking the immune system into perceiving infected cells as healthy. In certain autoimmune conditions, an imbalance in NKG2A’s function can contribute to disease progression. While an NKG2A bias can be protective by reducing inflammation, it can also prevent NK cells from eliminating autoreactive T cells that mistakenly attack healthy tissues.
Targeting NKG2A for Treatment
Given NKG2A’s role in immune evasion, scientists are investigating ways to manipulate this pathway for therapeutic purposes, particularly in cancer immunotherapy. The goal is to block or disable NKG2A, “releasing the brakes” on immune cells and allowing them to more effectively fight diseases. One promising approach involves using monoclonal antibodies designed to bind to NKG2A. These antibodies prevent NKG2A from interacting with HLA-E, removing the inhibitory signal and unleashing the anti-tumor activity of NK cells and T cells.
Monalizumab is a humanized anti-NKG2A antibody currently being evaluated in clinical trials for various cancers. This antibody aims to enhance immune responses against tumors. Combining NKG2A blockade with other immunotherapies, such as PD-1 or PD-L1 inhibitors, is also being explored for a more robust and sustained anti-tumor effect. This research holds potential for improving treatment outcomes for patients with cancer and other immune-related diseases.