The immune system functions as the body’s defense network, constantly working to identify and eliminate threats such as infections or abnormal cells. Within this complex system, T cells act as specialized soldiers, capable of recognizing and targeting specific dangers. For these T cells to respond effectively, they rely on precise communication signals. CD28 signaling represents a communication pathway that helps T cells receive the necessary instructions to mount a robust and appropriate immune response against invaders.
The Two-Signal Model of T Cell Activation
T cells require more than just recognizing a threat to become fully active and initiate an immune response. They operate on a “two-signal” model to ensure that their activation is precise and controlled, preventing unintended attacks on healthy body tissues. The first signal occurs when the T cell receptor (TCR) on the T cell surface binds to a specific antigen presented by another immune cell, known as an antigen-presenting cell (APC). This initial recognition provides the specificity for the immune response.
However, this first signal alone is often insufficient for full T cell activation. A second, co-stimulatory signal is also needed to confirm the presence of a genuine threat and to enhance the T cell’s response. Without this second signal, T cells may enter a state of unresponsiveness called anergy, or they might undergo programmed cell death, which helps to prevent autoimmune reactions where the immune system mistakenly attacks the body’s own cells.
CD28 and Its Binding Partners
CD28 is a protein found on the surface of T cells. It functions by interacting with specific molecules on the surface of antigen-presenting cells (APCs), acting as a “co-stimulatory” receptor.
The primary binding partners for CD28 are two related proteins called CD80 (also known as B7-1) and CD86 (also known as B7-2), which are expressed on APCs like dendritic cells, macrophages, and B cells. When a T cell encounters an APC presenting an antigen, CD28 on the T cell binds to CD80 or CD86 on the APC. This interaction provides the necessary second signal that complements the T cell receptor’s recognition of the antigen, thereby initiating full T cell activation.
How CD28 Signaling Boosts T Cell Function
Once CD28 on the T cell binds to CD80 or CD86 on an antigen-presenting cell, it triggers a series of internal events inside the T cell. This signaling amplifies the initial signal received through the T cell receptor, leading to a stronger immune response.
This signaling cascade activates various downstream pathways, which in turn activate transcription factors like NFAT and AP-1. These transcription factors then move into the nucleus of the T cell, where they promote the expression of genes involved in T cell proliferation, survival, and the production of important immune messengers. For instance, CD28 signaling enhances the production of interleukin-2 (IL-2), a cytokine referred to as T cell growth factor, which promotes T cell clonal expansion and differentiation. CD28 also increases the stability of IL-2 messenger RNA.
CD28 signaling contributes to the T cell’s metabolic reprogramming by increasing its glycolytic rate, providing the energy needed for growth and proliferation. It also helps T cells overcome cell cycle checkpoints, ensuring progression through cell division. By orchestrating these complex intracellular events, CD28 signaling ensures that T cells not only become activated but also multiply, survive longer, and produce the necessary molecules to effectively clear infections or eliminate cancerous cells.
CD28 in Immune Health and Therapeutic Applications
CD28 signaling plays a role in maintaining the balance of the immune system, contributing to effective immunity against pathogens and the prevention of autoimmune diseases. When CD28 signaling is dysregulated, it can contribute to the development of autoimmune conditions, where the immune system mistakenly attacks healthy tissues. Conversely, in cancer, CD28 signaling is beneficial for mounting an effective anti-tumor immune response, as it enhances the T cells’ ability to recognize and destroy cancer cells.
Understanding the mechanisms of CD28 signaling has paved the way for various therapeutic strategies. One major area is cancer immunotherapy, particularly with immune checkpoint inhibitors. For example, CTLA-4, a molecule structurally similar to CD28, also binds to CD80 and CD86, but it delivers an inhibitory signal, essentially acting as a “brake” on T cell activation. By blocking CTLA-4 with therapeutic antibodies, CD28 is allowed to bind more freely to CD80/CD86, thereby releasing the brakes on T cells and enhancing anti-tumor immunity.
Another therapeutic approach involves co-stimulatory blockade, which aims to suppress unwanted immune responses. Abatacept, for instance, is a soluble form of CTLA-4 that binds CD80 and CD86 with higher affinity than CD28, effectively preventing CD28-mediated co-stimulation. This strategy is used in autoimmune diseases like rheumatoid arthritis and in transplantation to prevent rejection, by dampening T cell activation and promoting immune tolerance. Researchers are exploring CD28 agonists, designed to directly activate CD28 and amplify T cell responses. These show potential in boosting anti-tumor immunity.