T cells are a component of the adaptive immune system that circulates throughout the body in a dormant state. Their activation is a tightly regulated process that transforms them from quiet patrollers into active participants in an immune response. This activation sequence functions as a multi-step authorization that prevents the immune system from mistakenly targeting the body’s own healthy tissues.
The First Requirement: Antigen Presentation
The activation of a T cell begins with a specific recognition event involving Antigen-Presenting Cells (APCs), such as dendritic cells. APCs act as sentinels, sampling their environment for foreign materials. When an APC encounters a pathogen, it internalizes it and breaks it down into smaller fragments called antigens.
These antigenic fragments are then displayed on the surface of the APC, cradled within a molecule called the Major Histocompatibility Complex (MHC). For a T cell to become activated, its T-cell receptor (TCR) must physically bind to this MHC-antigen complex. This precise interaction, often compared to a key fitting a specific lock, constitutes the first signal of T cell activation and confirms the T cell has found its target.
The Second Requirement: Co-stimulation
Following antigen recognition, a second signal known as co-stimulation is required to proceed with T cell activation. This signal serves as a confirmation step, ensuring the detected antigen is associated with genuine danger. This prevents T cells from activating in response to harmless substances or healthy self-cells.
The co-stimulatory signal is delivered through an interaction between molecules on the T cell and the APC. A primary example is the protein CD28 on the T cell binding to B7 molecules on the APC. The expression of B7 molecules on APCs increases significantly during inflammation or infection, signaling that the presented antigen is part of a legitimate threat. Antigen presentation alone is insufficient to trigger a full T cell response.
The Third Requirement: Cytokine Signaling
Once a T cell receives the first two signals, it requires further instructions to determine the nature of its response. This third signal is provided by cytokines, which are small proteins that act as chemical messengers. The specific cytokines in the local environment guide the T cell’s differentiation into a specialized effector cell tailored to the threat.
The type of cytokine signal received dictates the T cell’s function. For instance, the cytokine Interleukin-12 (IL-12) pushes a helper T cell to become a Type 1 helper (Th1) cell, which helps orchestrate a response against intracellular pathogens like viruses. In contrast, the presence of Interleukin-4 (IL-4) directs the T cell to become a Type 2 helper (Th2) cell, which is more effective at combating parasites. For CD8+ T cells, also called cytotoxic T cells, cytokines like IL-12 promote their survival and ability to kill infected cells.
Consequences of Incomplete Activation
The multi-signal activation process has built-in fail-safes. The most significant consequence of an incomplete sequence occurs when a T cell receives the first signal (antigen recognition) without the second signal (co-stimulation). This scenario induces a state of non-responsiveness known as T-cell anergy.
Anergy is a mechanism that contributes to self-tolerance, the immune system’s ability to ignore its own healthy tissues. Normal, healthy cells may occasionally present self-antigens on their MHC molecules, delivering Signal 1 to a T cell. However, because the healthy cell is not an activated APC and there is no inflammation, it does not express co-stimulatory molecules and cannot provide Signal 2.
When the T cell’s receptor is engaged without the co-stimulatory signal, the cell is turned off. An anergic T cell enters a state where it is unable to respond to future encounters with its specific antigen, even if both signals are present later. This process neutralizes potentially self-reactive T cells, preventing them from initiating an autoimmune attack.