CD28 Structure and Its Role in Immune System Function

The immune system requires checks and balances to mount an effective response against pathogens without damaging the body’s tissues. The protein CD28 functions as a co-stimulatory molecule on the surface of T-cells to help manage this process. When a T-cell encounters a threat, it needs more than one signal to become fully activated. CD28 provides a second, confirming signal necessary for a strong immune reaction, a function directly tied to its specific molecular structure.

The Architectural Blueprint of CD28

CD28 is a type I transmembrane protein, meaning it passes through the cell membrane once with distinct portions inside and outside the T-cell. On the cell surface, CD28 exists as a homodimer, a structure where two identical protein chains are linked by a disulfide bond. The protein is composed of 220 amino acids organized into several functional domains.

The portion of CD28 that extends outside the cell features a V-set domain from the immunoglobulin (Ig) superfamily, giving it structural similarities to antibodies. This extracellular domain is responsible for recognizing and binding to other molecules. It connects via a stalk region to the transmembrane domain, which anchors the protein within the T-cell’s outer membrane.

Inside the cell is the cytoplasmic tail, a short segment of 41 amino acids responsible for transmitting signals. While it lacks the ability to function as an enzyme, this tail contains specific sequences of amino acids known as motifs. These include a tyrosine-based motif (YMNM) and a proline-rich motif (PYAP), which act as docking sites for other signaling proteins.

CD28’s Molecular Handshake: Ligands and Binding

The function of CD28 begins with a specific interaction. Its extracellular IgV-like domain is designed to bind to two particular proteins: CD80 (B7.1) and CD86 (B7.2). These partner molecules, or ligands, are expressed on the surface of other immune cells called antigen-presenting cells (APCs). The V-set domain’s unique shape ensures that the activation signal is delivered only when a T-cell makes direct contact with an appropriate APC.

This molecular handshake is also thought to induce conformational changes within the CD28 homodimer. The interaction with CD80 or CD86 may cause a rearrangement of the dimer, preparing it to transmit signals across the cell membrane. This specificity ensures that the downstream effects of CD28 are tightly controlled and initiated only under the correct immunological circumstances.

How CD28 Structure Governs Immune Cell Activation

Once CD28 binds to its ligand on an antigen-presenting cell, the information is transmitted inside the T-cell via the cytoplasmic tail. The binding event triggers the phosphorylation of the tyrosine residue within the tail’s YMNM motif. This chemical modification acts like a switch, creating a new docking site for other proteins.

Signaling proteins inside the T-cell containing SH2 domains can recognize and bind to this phosphorylated motif. For instance, the docking of the enzyme PI3K (phosphoinositide 3-kinase) to this site initiates biochemical reactions that promote cell survival and metabolism. The proline-rich PYAP motif similarly recruits other signaling proteins that contain SH3 domains.

The result of these recruited proteins is the delivery of the “second signal” for T-cell activation. This signal works with the primary signal from the T-cell receptor to enhance the cell’s response. It promotes proliferation, the production of signaling molecules called cytokines, and prevents the T-cell from entering a dormant state known as anergy.

Implications of CD28 Structure in Medical Science

Understanding CD28 structure has direct applications in medicine for treating immune system diseases. When CD28 signaling is overactive, it can contribute to autoimmune disorders by causing T-cells to attack the body’s tissues. Therapies have been developed that block the interaction between CD28 and its ligands, which dampens the co-stimulatory signal and reduces T-cell activation.

Conversely, in cancer treatment, the goal is to enhance the T-cell response. Knowledge of CD28’s signaling mechanism has aided the development of Chimeric Antigen Receptor (CAR) T-cell therapy. In this approach, a patient’s T-cells are engineered to recognize cancer cells by incorporating the gene for CD28’s cytoplasmic tail into the synthetic CAR receptor.

This structural inclusion means that when the engineered T-cell binds to a cancer cell, the built-in CD28 domain provides the co-stimulatory signal needed for activation and anti-tumor activity. The design leverages the function of the CD28 tail’s signaling motifs to turn the T-cell into a more effective killer of malignant cells.