In the immune system’s communication network, certain proteins act as messengers to coordinate cellular activity. One such molecule is CD137 ligand, or CD137L. It functions like a specific handshake that initiates a conversation between defensive cells to mount an effective response against threats. This interaction is a significant point of interest in immunology, driving research into how it can be harnessed for medical treatments.
The CD137L and CD137 Signaling Pair
CD137L is a ligand, a protein that binds to a specific partner receptor to transmit a signal. Its dedicated receptor is CD137, also known as 4-1BB. Their interaction is a carefully orchestrated event that depends on which cells are expressing each component, ensuring signals are delivered only to the intended cellular targets.
The expression of these proteins is tightly regulated. CD137L is found on the surface of antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B cells. These APCs are responsible for processing threats and presenting parts of them to other immune cells.
Conversely, the CD137 receptor is not always present on its target cells. Its expression is induced on T cells and Natural Killer (NK) cells only after they have been activated by an encounter with a pathogen. This controlled expression ensures the powerful signal from the CD137L-CD137 interaction occurs only when needed, preventing inappropriate immune activation.
Function in Immune System Activation
The binding of CD137L to the CD137 receptor is co-stimulation, a secondary signal required to fully activate T cells. The initial signal occurs when a T cell recognizes an antigen presented by an APC, but this is often insufficient for a robust response. The CD137L-CD137 interaction provides a necessary second verification step, confirming the threat is genuine and a powerful counter-attack is warranted.
Once engaged, this pairing triggers a cascade of events inside the T cell. The binding brings multiple CD137 receptors together, which recruit adaptor proteins like TRAF1 and TRAF2. This assembly, the signalosome, activates downstream pathways that alter the T cell’s function and drive it to full activation.
The primary outcomes of this co-stimulatory signal enhance the immune response. It causes T cell proliferation, meaning activated T cells divide rapidly to create an army of clones specific to the threat. The signal also promotes the survival of these T cells and is instrumental in developing memory T cells, which provide long-term immunity by “remembering” a pathogen for future encounters.
Therapeutic Applications in Oncology
Cancer cells often develop mechanisms to evade or suppress the immune system, allowing them to grow unchecked. Immunotherapy seeks to counteract these strategies by reinvigorating a patient’s immune cells to attack tumors, and the CD137 pathway is a promising target for this treatment.
Researchers have developed drugs, known as agonist antibodies, that artificially stimulate the CD137 receptor. These drugs bind directly to the receptor on T cells, providing the co-stimulatory signal needed for their activation. This approach is designed to “press the gas pedal” on anti-tumor T cells, overcoming suppressive signals from the cancer.
Two examples of CD137 agonist antibodies investigated in clinical trials are urelumab and utomilumab. These therapies are designed to boost the activity of CD8+ T cells, which are effective at killing cancer cells. By providing a strong activation signal, these drugs aim to enhance the anti-cancer immune response.
Beyond Cancer and Therapeutic Considerations
The influence of the CD137L/CD137 pathway extends beyond cancer. In viral infections, this signaling is beneficial, promoting T-cell responses needed to clear the virus. However, the pathway can also be a factor in autoimmune diseases, where its over-activation may contribute to misguided attacks on the body’s healthy tissues.
Manipulating this pathway for therapeutic benefit is not without risks. The same powerful immune activation that destroys cancer cells can also lead to significant side effects. Overstimulating the immune system with CD137 agonist antibodies can cause immune-related adverse events, where activated T cells attack healthy organs.
A concerning side effect observed in early trials of some CD137 agonists was hepatotoxicity, or liver inflammation. This occurs because the systemic activation of T cells is not confined to the tumor environment. This risk requires careful management in the development and administration of these therapies, balancing potent anti-tumor activity with protecting the patient from harmful autoimmune-like reactions.