The immune system protects the body from foreign invaders like bacteria and viruses. This complex system relies on intricate communication between its cells to coordinate effective responses. Among the many molecules involved in this cell-to-cell dialogue, CD28 and B7 are important players, orchestrating interactions for proper immune function.
The Immune System’s Crucial Connection
CD28 is a protein receptor found on the surface of T cells, a type of white blood cell central to adaptive immunity. Its counterparts, the B7 molecules—B7-1 (CD80) and B7-2 (CD86)—are expressed on specialized antigen-presenting cells (APCs). These APCs include dendritic cells, macrophages, and B cells, which display foreign fragments to T cells.
The interaction between CD28 on T cells and B7 molecules on APCs provides a secondary signal known as costimulation, necessary for full T cell activation. This is part of the “two-signal model” of T cell activation. The first signal occurs when the T cell receptor (TCR) on the T cell recognizes a specific antigen presented by a major histocompatibility complex (MHC) molecule on the APC.
Without this second costimulatory signal, the T cell may become anergic, entering a state of unresponsiveness to the antigen. This mechanism helps prevent the immune system from mistakenly attacking the body’s own healthy tissues, as T cells require both specific antigen recognition and a “danger” signal (costimulation) to become fully activated.
Activating the Body’s Defenders
The binding of CD28 to B7 molecules initiates a cascade of events inside the T cell, leading to its full activation, proliferation, and differentiation into various effector cells. This binding triggers intracellular signaling pathways, including the activation of phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) family kinases. These pathways lead to changes in gene expression within the T cell.
A consequence of this signaling is the increased production of cytokines, particularly Interleukin-2 (IL-2). IL-2 acts as a growth factor, promoting the proliferation and survival of T cells, allowing for the expansion of antigen-specific T cell populations. This amplification is necessary to mount an effective adaptive immune response against pathogens or abnormal cells.
Without the costimulatory signal, the T cell response remains weak or absent, even if the T cell receptor recognizes the antigen. This highlights the pathway’s importance in ensuring an effective immune response.
Implications in Health and Disease
Dysregulation of the CD28-B7 pathway can have implications for health, contributing to both autoimmune diseases and cancer. In autoimmune conditions, such as rheumatoid arthritis or multiple sclerosis, excessive CD28-B7 signaling can lead to T cells mistakenly attacking the body’s own tissues. This overactivity can drive chronic inflammation and tissue damage.
Conversely, cancer cells can exploit this pathway to evade immune detection and destruction. Some tumors may reduce B7 molecule expression on their surface, preventing T cell activation and allowing them to escape immune surveillance. Additionally, tumors can upregulate molecules like CTLA-4 (Cytotoxic T-Lymphocyte-Associated protein 4), which also binds to B7 molecules but delivers an inhibitory signal to T cells.
CTLA-4 has a higher affinity for B7 molecules than CD28, allowing it to outcompete CD28 for binding and effectively “put the brakes” on T cell activity. The balance between the stimulatory signals from CD28 and the inhibitory signals from CTLA-4, both mediated by B7 molecules, is important for maintaining immune homeostasis. Disruption of this balance can lead to a failure of immune tolerance, contributing to the progression of diseases like cancer or the onset of autoimmune disorders.
Targeting the Pathway for Treatment
Understanding the CD28-B7 pathway has opened avenues for developing therapeutic strategies. In autoimmune diseases, drugs like Abatacept (Orencia) are designed to block the CD28-B7 interaction. Abatacept is a fusion protein that mimics CTLA-4, binding to B7-1 (CD80) and B7-2 (CD86) molecules on APCs.
By doing so, Abatacept prevents CD28 from binding to B7, inhibiting the necessary costimulatory signal for T cell activation. This selective blockade reduces T cell proliferation and the production of pro-inflammatory cytokines, dampening the overactive immune response seen in conditions like rheumatoid arthritis.
In cancer immunotherapy, the focus is often on restoring or enhancing anti-tumor immunity by modulating this pathway. Immune checkpoint inhibitors, such as those targeting CTLA-4 or the PD-1/PD-L1 pathway, aim to release the “brakes” on T cells. By blocking inhibitory signals, these therapies allow the stimulatory CD28-B7 signal to dominate, activating T cells to recognize and attack cancer cells more effectively. This approach has shown promise in various cancers, including melanoma.