The adaptive immune system provides the body with a targeted defense mechanism against invading pathogens. T lymphocytes, often called T cells, are responsible for recognizing and eliminating specific threats. Because these cells possess the power to destroy, their activation must be precisely controlled to prevent them from mistakenly attacking the body’s own tissues. This precision is achieved through a molecular security system that requires T cells to receive not just a recognition signal, but a second, independent confirmation signal. This two-step verification process, known as co-stimulation, ensures that T cells are fully mobilized only when a danger is confirmed by specialized immune cells. This safeguard is a foundational concept in immunology, governing the difference between a protective immune response and harmful self-attack.
Defining T Cell Activation Requirements
Full T cell activation operates according to the Two-Signal Hypothesis. The first signal provides the necessary specificity, ensuring the T cell targets the correct invader. This Signal 1 is initiated when the T Cell Receptor (TCR) on the T cell surface recognizes and binds to a specific antigen fragment. This fragment is held within the Major Histocompatibility Complex (MHC) molecule, which is displayed on the surface of an Antigen-Presenting Cell (APC).
However, Signal 1 alone is not sufficient to fully launch an immune response. If a T cell receives Signal 1 alone, it often enters a state of non-responsiveness called anergy, or it may even be deleted from the immune repertoire. This outcome prevents T cells that mistakenly recognize a self-antigen from causing damage. To proceed to full activation, the T cell must simultaneously receive a second, non-specific signal, known as co-stimulation.
This co-stimulatory signal confirms that the presented antigen is part of a genuine threat. This second signal is delivered through specialized receptor-ligand pairs that bridge the T cell and the APC. This synchronized requirement ensures that T cells only become fully active when they encounter a foreign antigen presented by an APC that has been activated by signs of danger or inflammation.
The CD28 B7 Co-Stimulation Signal
The interaction between the CD28 receptor on the T cell and its B7 ligands on the APC is often referred to as the immune system’s handshake. The B7 family consists primarily of two molecules, B7-1 (CD80) and B7-2 (CD86), which are expressed on the surface of professional APCs. When the T cell is engaged by Signal 1, the simultaneous binding of CD28 to B7 delivers Signal 2, resulting in a change in T cell behavior.
This co-stimulatory signal is a survival and proliferation cue for the T cell. Inside the T cell, the engagement of CD28 recruits intracellular signaling enzymes. This recruitment triggers a cascade that synergizes with the signaling initiated by the TCR, amplifying the overall activation signal. The result is the rapid transcription of genes necessary for an immune response.
One of the most immediate consequences is the massive production of the growth factor Interleukin-2 (IL-2). IL-2 is secreted by the activated T cell, driving rapid cell division and clonal expansion. This process allows a small number of antigen-specific T cells to quickly multiply into a large population capable of clearing the infection. Without the CD28-B7 handshake, the T cell produces minimal amounts of IL-2, leading to an unproductive encounter and the state of anergy.
The Immune System’s Regulatory Brake
While CD28 provides the necessary “go” signal, the immune system employs a regulatory brake to prevent over-activation, which is mediated by a receptor called Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4). CTLA-4 delivers an inhibitory signal. The expression of CTLA-4 is rapidly upregulated and moved to the cell surface shortly after T cell activation begins.
CTLA-4 competes directly with CD28 for binding to the B7 ligands on the APC. This competition is heavily weighted in favor of the inhibitory molecule, as CTLA-4 possesses a significantly higher binding affinity for B7 than CD28. By binding B7 more tightly and more frequently, CTLA-4 effectively sequesters the activating ligands away from CD28, dampening the co-stimulatory Signal 2.
CTLA-4 actively suppresses the immune response through several mechanisms. It can deliver a direct inhibitory signal to the T cell, limiting IL-2 production and proliferation. Furthermore, CTLA-4 on regulatory T cells (Tregs) can physically pull B7 molecules off the APC surface and internalize them, a process called trans-endocytosis. This action starves nearby conventional T cells of the necessary co-stimulation.
Manipulating the Handshake for Therapy
The balance between the activating CD28 signal and the inhibitory CTLA-4 signal presents a target for medical intervention. By manipulating this handshake, clinicians can selectively enhance or suppress T cell responses. One therapeutic strategy involves blocking the activating signal to treat conditions where the immune system is overactive.
For instance, in autoimmune diseases or organ transplantation, the goal is to suppress T cell activity to prevent the immune system from attacking self-tissue or the graft. Drugs like the fusion protein Abatacept (CTLA-4 Ig) are engineered to mimic CTLA-4, binding to B7 ligands on the APCs with high affinity. This action prevents the natural CD28-B7 handshake from occurring, effectively blocking Signal 2 and inducing T cell anergy.
Conversely, in cancer immunotherapy, the aim is to release the immune system’s brakes to allow T cells to attack tumor cells more effectively. Checkpoint inhibitor drugs, such as anti-CTLA-4 antibodies, are designed to block the CTLA-4 receptor itself. This blockade prevents CTLA-4 from delivering its inhibitory signal, allowing the CD28-B7 handshake to proceed unimpeded and boosting the T cell response against the tumor.