T cells are specialized white blood cells that form a central part of the adaptive immune system, providing a targeted defense against pathogens and abnormal cells. These lymphocytes possess unique receptors that allow them to recognize specific threats, such as virus-infected or cancer cells, with high precision. To prevent uncontrolled responses that could damage healthy tissues, T cells are subject to stringent regulatory mechanisms. The immune system uses a sophisticated system of checks and balances to ensure T cells only launch an attack when confirmed.
The Requirement for T Cell Activation
Optimal T cell activation is governed by a fundamental biological principle known as the “Two-Signal Model.” The first signal, which provides specificity, is delivered when the T cell receptor (TCR) recognizes a foreign fragment, or antigen, presented on a Major Histocompatibility Complex (MHC) molecule of an antigen-presenting cell (APC). However, this first signal alone is insufficient to trigger a full immune response.
If a T cell receives only this specific signal without further confirmation, the cell typically enters a state of unresponsiveness called anergy. Anergy is a protective mechanism that ensures T cells do not react to self-antigens, thereby maintaining self-tolerance. To become fully activated and mount a sustained response, the T cell must simultaneously receive a second, non-specific signal, known as co-stimulation.
CD28 and the Co-Stimulatory Mechanism
The CD28 receptor on the T cell surface provides the co-stimulatory Signal 2, acting as the necessary “go” signal for activation. CD28 is constitutively expressed on most T cells. It interacts with its specific ligands, B7-1 (CD80) and B7-2 (CD86), which are expressed on the surface of activated APCs, such as dendritic cells and macrophages.
The binding of CD28 to its B7 ligands initiates a powerful cascade of biochemical events within the T cell. Upon engagement, the cytoplasmic tail of CD28 recruits and activates intracellular signaling molecules like Phosphatidylinositol 3-kinase (PI3K). This activation of the PI3K/Akt pathway promotes cell survival and lowers the threshold of the TCR signal, making the T cell highly responsive to the antigen.
CD28 signaling also enhances the production of T cell growth factors, notably Interleukin-2 (IL-2), and drives the expression of transcription factors like NF-κB and AP-1. These factors promote rapid proliferation and differentiation, allowing the activated T cell to clone itself into an army of effector cells. Without the CD28 co-stimulatory signal, the T cell cannot achieve the sustained changes required to mount a productive immune response.
Regulating T Cell Signals
While CD28 provides the necessary activating boost, the immune system employs inhibitory co-stimulatory molecules to act as a brake, preventing excessive or prolonged T cell activity. The most prominent of these negative regulators are Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) and Programmed cell death protein 1 (PD-1), which together help maintain immune homeostasis. CTLA-4 is upregulated on the T cell surface shortly after activation and competes directly with CD28 for the B7-1 and B7-2 ligands.
CTLA-4 binds to the B7 ligands with a significantly higher affinity than CD28, effectively outcompeting the activating signal and shutting down T cell proliferation early in the response. This mechanism primarily regulates the initial priming of T cells in lymphoid tissues.
PD-1 operates with a different mechanism, binding to its ligands, PD-L1 and PD-L2, which are often expressed on tumor cells or cells in inflamed tissues. PD-1 interferes with the downstream signaling pathways activated by CD28, essentially disabling the “go” signal. Ligation of PD-1 recruits an enzyme called SHP2, which prevents the full activation of the PI3K/Akt pathway. This inhibitory signaling tempers T cell activity in the peripheral tissues, preventing collateral damage and representing a key pathway exploited by cancer cells to evade immune destruction.
Applying Co-Stimulation in Medicine
The balance between the activating CD28 pathway and the inhibitory CTLA-4 and PD-1 pathways is a major focus of modern medicine. In cancer immunotherapy, the goal is to unleash the T cells’ natural killing ability against tumors by blocking the inhibitory signals. Therapeutic agents known as immune checkpoint inhibitors are designed to specifically block CTLA-4 or PD-1, effectively releasing the brakes on the T cell response.
Blocking CTLA-4 allows T cells to continue receiving the CD28 activating signal, promoting a larger and more sustained population of T cells to attack the tumor. Blocking PD-1 restores the function of T cells that have become exhausted in the tumor microenvironment due to prolonged exposure to PD-L1 on cancer cells. The success of these checkpoint inhibitors has revolutionized cancer treatment by harnessing the body’s immune system.
Conversely, in autoimmune diseases and organ transplantation, the aim is to dampen an overactive T cell response. One therapeutic strategy is to block the CD28 co-stimulatory signal, inducing anergy in T cells that recognize self-antigens or the transplanted organ. Drugs like Abatacept, a fusion protein mimicking CTLA-4, bind to the B7 ligands on APCs, preventing them from engaging CD28 and turning off the T cell activation pathway. This targeted manipulation of the CD28/B7 axis allows clinicians to selectively suppress harmful immune responses while preserving general immune function.