The immune system uses checks and balances to avoid attacking the body’s healthy tissues. A primary safety mechanism is the requirement for costimulatory signals to activate T-cells, the main soldiers of the adaptive immune response. This system functions like two-factor authentication; recognizing a threat is not enough to launch an attack. A second, independent signal must confirm the threat is genuine. Without this confirmation, the T-cell stands down, preventing accidental activation against harmless substances or the body’s cells. This dual-signal requirement ensures the immune system’s power is used only when necessary.
The Two-Signal Requirement for T-Cell Activation
For a T-cell to become fully activated, it must receive two distinct signals from an antigen-presenting cell (APC). APCs act as scouts, sampling their environment for invaders like bacteria or viruses. When an APC finds a pathogen, it displays a piece of it, called an antigen, on its surface using a major histocompatibility complex (MHC) molecule. This presentation of the antigen to a T-cell is the first signal.
The first signal provides specificity, ensuring only T-cells with a matching T-cell receptor (TCR) are engaged. This interaction confirms the T-cell recognizes the potential threat, but it is insufficient for activation. The APC must also provide a second, confirmatory “danger” signal, which tells the T-cell that the antigen comes from a genuine threat.
This second signal is a costimulatory interaction, with the most well-understood example being the binding of the B7 molecule on the APC to the CD28 protein on the T-cell. This B7-CD28 connection only occurs if the APC has been activated by inflammatory molecules from pathogens. The successful delivery of both signals prompts the T-cell to multiply and develop its functions to eliminate the threat.
Consequences of Inadequate Costimulation
The immune system has a fail-safe for when a T-cell receives the first signal without the second. This happens when a T-cell encounters a self-antigen on a healthy APC that is not displaying the B7 costimulatory molecule. The T-cell recognizes a part of the body but receives no “danger” signal to confirm a threat.
When Signal 1 is delivered without Signal 2, the T-cell does not activate and instead enters a state of unresponsiveness called anergy. An anergic T-cell is not killed but is switched off, unable to respond even if it later encounters both signals. This process is a mechanism of peripheral tolerance, preventing the immune system from attacking the body’s tissues.
By rendering self-reactive T-cells harmless, anergy protects against autoimmunity. It ensures that T-cells that may have escaped initial screening in the thymus do not cause damage. This functional inactivation is a direct consequence of inadequate costimulation.
The Brakes of the Immune System: Coinhibitory Signals
Just as costimulation acts as a “gas pedal” for a T-cell response, coinhibitory signals function as the “brakes” to control and terminate it. These signals are necessary to prevent an immune response from continuing indefinitely, which could cause excessive inflammation and tissue damage. Once a threat is neutralized, the immune system must return to a state of balance.
This regulation is managed by coinhibitory receptors that appear on the surface of activated T-cells. Two primary receptors are Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) and Programmed Cell Death protein 1 (PD-1). When these receptors bind to their partner molecules, they transmit inhibitory signals that override the initial activation signals, shutting down T-cell activity.
CTLA-4 functions during the initial activation phase in lymph nodes. It competes with the CD28 receptor to bind to B7 molecules on APCs. Because CTLA-4 binds to B7 more strongly than CD28, it can outcompete the activating signal and dampen the T-cell response from the start.
In contrast, PD-1 acts later in the immune response within peripheral tissues, helping to terminate the actions of T-cells already fighting an infection. This active inhibition is distinct from anergy. It is not a failure to start but a deliberate command to stop an ongoing response.
Therapeutic Manipulation of Costimulatory Pathways
Understanding the “gas” and “brake” pedals of T-cell activation has enabled therapies that either enhance or suppress immune responses. In oncology, the focus is on releasing the immune system’s brakes to allow it to attack cancer cells. Tumors can exploit coinhibitory pathways by expressing the ligands for PD-1, which tells approaching T-cells to stand down.
Cancer treatments known as checkpoint inhibitors are designed to block these “brake” signals. These drugs use antibodies to obstruct molecules like CTLA-4 or PD-1, preventing them from binding to their partners. This action releases the brakes on T-cells, allowing them to recognize and destroy malignant cells they previously ignored.
Conversely, for autoimmune diseases or to prevent organ transplant rejection, the goal is to suppress an overactive immune response. Therapies for these conditions interfere with the “gas pedal” by blocking the CD28-B7 costimulatory pathway. This prevents T-cells from receiving the second activation signal. This strategy induces a state similar to anergy, calming the immune system and preventing it from attacking the body’s tissues or a transplanted organ.