The Fas/FasL system is a highly regulated biological mechanism that dictates the life or death of a cell via the extrinsic route of programmed cell death, known as apoptosis. The core components are Fas, a receptor protein on the cell surface, and Fas Ligand (FasL), the signaling molecule that binds to it. This pair transmits the “death signal” from the outside to the inside of a cell. Functioning as a cellular quality control system, the Fas/FasL pathway ensures the timely removal of damaged, infected, or unneeded cells, which is essential for immune system regulation and tissue development.
How the Death Signal is Transmitted
The process begins when the FasL protein on one cell binds to the Fas receptor protein on the surface of a target cell. Both FasL and Fas typically exist as trimers, and this binding causes the Fas receptors to cluster together on the target cell membrane. This clustering activates the Fas receptor’s internal segment, which contains a specific region called the death domain.
The activated death domain then recruits an adaptor protein known as FADD (Fas-Associated Death Domain). FADD acts as a bridge, bringing the inactive form of an initiator enzyme, procaspase-8, into the complex. The combined structure of Fas, FADD, and procaspase-8 is referred to as the Death-Inducing Signaling Complex (DISC).
Within the newly formed DISC, multiple procaspase-8 molecules are brought into close proximity, allowing them to cut and activate each other. This self-cleavage produces active caspase-8, which is then released from the DISC into the cell’s interior, the cytosol. Once released, caspase-8 proceeds to activate executioner caspases, such as caspase-3, which dismantle the cell’s internal components.
Maintaining Balance in the Immune System
The primary healthy function of the Fas/FasL pathway is to maintain immune system stability, a process known as immune homeostasis. After the body clears an infection, activated immune cells like T-lymphocytes are no longer required and must be eliminated to prevent unnecessary inflammation. The Fas/FasL interaction mediates this necessary cleanup through a process called Activation-Induced Cell Death (AICD).
T-cells that have been repeatedly stimulated or have completed their task upregulate the expression of both Fas and FasL on their surfaces. This allows them to signal for their own destruction, either by interacting with FasL on their own surface or by engaging FasL on a neighboring immune cell. This self-limiting mechanism controls the number of circulating lymphocytes and terminates the immune response.
The pathway also plays a role in establishing peripheral tolerance by eliminating self-reactive T-cells. If a T-cell escapes primary checks in the thymus and recognizes the body’s own proteins, the Fas/FasL system deletes it before it can trigger an autoimmune attack. This regulated removal of self-attacking cells is essential for preventing autoimmune disease development.
Connection to Uncontrolled Cell Growth
Defects in the Fas/FasL pathway are frequently observed in various cancers, allowing tumor cells to escape destruction by the immune system. One common evasion strategy involves the cancer cell reducing or losing the Fas receptor on its surface. For example, Fas expression is decreased in many lung and colon tumors, rendering the cells resistant to the FasL signal delivered by cytotoxic T-lymphocytes (CTLs).
Some tumor cells interfere with signaling by producing decoy receptors, such as Decoy Receptor 3 (DcR3). This secreted protein binds to FasL, sequestering the death signal before it can reach the Fas receptor on the cell membrane, thus blocking apoptosis. This strategy ensures the tumor cells survive even when exposed to high concentrations of the death ligand.
Another mechanism, sometimes called the “Fas counterattack,” involves certain tumor cells overexpressing FasL themselves. When an immune cell like a CTL attempts to kill the tumor, the tumor cell’s FasL binds to the Fas receptor on the CTL, inducing apoptosis in the immune cell instead of itself. This turns the immune system’s weapon against the immune system, leading to immune evasion and continued proliferation.
Connection to Self-Attacking Diseases
A failure in the Fas/FasL pathway’s ability to eliminate unwanted immune cells can result in self-attacking diseases. When the mechanism for Activation-Induced Cell Death is compromised, lymphocytes that should have been cleared after an immune response remain in circulation. This uncontrolled survival leads to an accumulation of immune cells, causing the lymph nodes and spleen to enlarge, a condition known as lymphoproliferation.
Genetic defects in the Fas gene itself are the most common cause of Autoimmune Lymphoproliferative Syndrome (ALPS), a disorder characterized by this failure of lymphocyte apoptosis. Patients with ALPS accumulate a characteristic population of T-cells that lack specific surface markers (CD4 and CD8) and are called double-negative T-cells. The persistence of these self-reactive lymphocytes leads to autoimmune conditions where the immune system attacks the body’s own tissues. Common manifestations include autoimmune cytopenias, where antibodies attack blood components like red blood cells or platelets.