The immune system is the body’s defense mechanism, constantly working to identify and neutralize foreign invaders like bacteria, viruses, and abnormal cells. Among its diverse components, T cells are central players. These specialized white blood cells recognize specific threats and coordinate targeted responses to eliminate them, safeguarding overall health. For T cells to effectively mount such defenses, they require precise signals that initiate their activation and direct their specialized functions.
Understanding T Cells and Immune Activation
T cells (T lymphocytes) are white blood cells that develop in the thymus and play a central role in adaptive immunity, the body’s tailored defense against specific threats. Each T cell is programmed to recognize a particular foreign particle, known as an antigen. Once activated, T cells work to eliminate infected cells or cancer cells, or they send signals to direct other immune cells to fight the intruder.
T cells require multiple signals for proper activation, ensuring a precise and robust immune response. The initial signal, “Signal One,” occurs when a T cell receptor (TCR) binds to an antigen presented by a major histocompatibility complex (MHC) molecule on an antigen-presenting cell (APC). This binding triggers initial T cell activation, but this first signal alone is often insufficient for a full and sustained immune response, potentially leading to T cell unresponsiveness or anergy. Additional signals are necessary for complete T cell activation and to prevent inappropriate immune reactions.
CD28: The Co-stimulator
CD28 is a molecule on T cells that provides a “second signal” for their full activation. This co-stimulatory molecule is expressed on approximately 80% of human CD4+ T cells and about 50% of CD8+ T cells. Its presence ensures T cells become fully active only when they encounter both a specific antigen and additional signals, preventing unintended immune responses.
CD28 binds to specific ligands, CD80 (B7-1) and CD86 (B7-2), found on antigen-presenting cells (APCs). When the T cell receptor (TCR) engages an antigen, the simultaneous binding of CD28 to its ligands amplifies and sustains the initial activation signal. This interaction leads to phosphorylation of tyrosine residues in CD28’s cytoplasmic domain, which in turn recruits signaling enzymes like phosphatidylinositol 3-kinase (PI3K). The coordinated action of TCR signaling and CD28 co-stimulation results in the full activation of key downstream enzymes, such as phospholipase C-gamma (PLC-gamma), essential for robust T cell responses.
CD28’s Role in Shaping Immune Responses
CD28 co-stimulation significantly impacts the behavior and functions of activated T cells. Following activation, CD28 signaling drives rapid T cell proliferation, leading to clonal expansion—an increase in the number of antigen-specific T cells. This expansion ensures a sufficient force to combat the perceived threat.
Beyond proliferation, CD28 guides the differentiation of T cells into specialized effector cells. It promotes the development of helper T cells (CD4+ T cells) that orchestrate immune responses by activating other immune cells, and cytotoxic T lymphocytes (CD8+ T cells) that directly eliminate infected or cancerous cells. CD28 signaling enhances the production of cytokines, such as interleukin-2 (IL-2), which is a growth factor for T cells and further fuels their expansion and differentiation. CD28 co-stimulation contributes to the formation of long-lasting memory T cells, which are capable of a quicker and stronger response upon subsequent encounters with the same pathogen, providing durable protection.
CD28 in Immune Health and Disease
The proper functioning of CD28 is fundamental for effective immunity against infections and cancer. Its signaling ensures T cells are adequately activated to clear pathogens and eliminate malignant cells, contributing to overall immune health. Dysregulation of CD28 signaling can lead to various immune disorders.
In autoimmune diseases, an overactive CD28 pathway can contribute to the immune system mistakenly attacking the body’s own tissues. For example, therapies like abatacept (CTLA-4-Ig) work by blocking the CD80/CD86 ligands from binding to CD28, thereby reducing excessive T cell activation and inflammation in conditions such as rheumatoid arthritis. Conversely, in chronic infections or cancer, insufficient or altered CD28 signaling can lead to T cell exhaustion or anergy, where T cells become unresponsive and unable to effectively fight the disease. Understanding these pathways has led to the development of immunotherapies that either block CD28 activity to suppress overactive immune responses or enhance it to boost anti-tumor immunity.