HLA-E: Its Role in Immunity, Pregnancy, and Cancer
This article examines the HLA-E protein, a key immune modulator whose inhibitory signal is vital for health but can also be subverted in disease.
Human Leukocyte Antigen E (HLA-E) is a specialized protein on the surface of most cells in the body, functioning like a “do not disturb” sign for the immune system. This molecule plays a regulatory role, helping to maintain a balance between attacking threats and protecting the body’s own tissues. By signaling to specific immune cells, HLA-E prevents inappropriate immune reactions, which is a part of the body’s system for self-tolerance.
HLA-E’s Place in the Immune System
The Human Leukocyte Antigen (HLA) system, also known as the Major Histocompatibility Complex (MHC), is the body’s method for distinguishing its own healthy cells from foreign or infected ones. The “classical” HLA molecules, such as HLA-A, HLA-B, and HLA-C, function by presenting small pieces of proteins from within the cell to the immune system. This process alerts immune cells, like T cells, to the presence of pathogens or cellular abnormalities.
In contrast, HLA-E belongs to a group known as “non-classical” HLA molecules. Unlike its classical counterparts, HLA-E’s main role is not to present a wide variety of protein fragments. Instead, it has a specialized function focused on regulation, presenting a very limited set of peptides derived from other HLA class I molecules. Its limited variability across the human population highlights its conserved function.
The Mechanism of Immune Inhibition
HLA-E’s primary function is to regulate the activity of Natural Killer (NK) cells, a component of the innate immune system. NK cells are tasked with identifying and eliminating stressed, infected, or cancerous cells without prior sensitization, making them a rapid first line of defense. Their potent killing ability requires strict control to prevent damage to healthy cells.
This regulation occurs when HLA-E interacts with an inhibitory receptor on NK cells, known as NKG2A/CD94. When a healthy cell displays normal levels of HLA-E, the molecule binds to this receptor on a patrolling NK cell. This engagement transmits a powerful “off” signal into the NK cell.
This inhibitory signal instructs the NK cell to stand down and leave the healthy cell unharmed. The constant presence of HLA-E serves as a marker of health. NK cells are meant to target only those cells that have lost this protective signal, which can happen during a viral infection or cancerous transformation.
Role in Pregnancy and Fetal Protection
The inhibitory function of HLA-E is important during pregnancy. A developing fetus is genetically distinct from the mother and could be recognized as “foreign” by her immune system. This could trigger an immune attack similar to organ transplant rejection.
To prevent this, cells of the placenta, specifically the extravillous trophoblast cells that invade the uterine wall, express high levels of HLA-E. These placental cells come into direct contact with the mother’s immune cells, including a large population of uterine NK cells.
The abundance of HLA-E on these placental cells serves as a protective shield. As maternal NK cells encounter the fetal-derived trophoblast cells, the HLA-E binds to their inhibitory NKG2A/CD94 receptors. This interaction delivers the “do not attack” signal, calming the maternal NK cells and ensuring the successful gestation of the fetus.
Involvement in Cancer and Viral Infections
Diseases can exploit the protective mechanism of HLA-E to evade the immune system. Many types of cancer cells increase their surface expression of HLA-E, using it as a shield. This allows them to send an inhibitory signal to NK cells, preventing the cancer cells from being recognized and destroyed.
This immune evasion strategy is also used by some viruses. For instance, human cytomegalovirus (CMV) can force an infected host cell to continue expressing HLA-E. This maintains the “do not disturb” signal to NK cells, allowing the virus to hide and replicate without triggering an immune response.
Therapeutic Targeting of HLA-E
Understanding HLA-E’s role in cancer has led to new immunotherapies. These treatments are designed to counteract this immune escape mechanism, unmasking tumors and making them vulnerable to attack.
A primary strategy uses monoclonal antibodies, a type of checkpoint inhibitor, to block the NKG2A receptor on NK and T cells. By binding to this receptor, the antibody prevents HLA-E on a tumor cell from engaging with it. This action severs the inhibitory signal the cancer cell uses to protect itself.
With the “off” switch disabled, the NK cell’s natural functions are unleashed, allowing it to eliminate the malignant cell. Clinical trials are investigating NKG2A-blocking antibodies, such as monalizumab, as a way to restore the immune system’s ability to fight various cancers.