CD28 is a protein on the surface of T cells that acts as an essential “go” signal for the immune system. Without it, T cells that encounter a threat often fail to fully activate, leaving the immune response incomplete. It sits on nearly all T cells at birth and plays a central role in determining whether the body mounts a strong defense against infections, tolerates a transplanted organ, or mistakenly attacks its own tissues.
How CD28 Activates T Cells
T cells need two signals to turn on. The first comes when a T cell’s receptor recognizes a piece of a pathogen or abnormal cell. But that first signal alone isn’t enough. CD28 provides the critical second signal, called costimulation, that tells the T cell: “Yes, this is real. Go ahead and respond.” Without this second signal, the T cell may become unresponsive or die, a safeguard that helps prevent unnecessary immune reactions.
CD28 delivers this costimulatory signal by binding to two partner molecules, called B7-1 and B7-2, found on the surface of immune cells that present threats to T cells (known as antigen-presenting cells). These partner molecules appear on cells like dendritic cells, macrophages, and activated B cells. When CD28 locks onto B7-1 or B7-2, it triggers a cascade of internal signals that push the T cell to multiply, survive longer, and produce the chemical messengers needed to coordinate an immune attack.
The Built-In Brake: CTLA-4
The immune system doesn’t just have an accelerator. It also has a brake that competes directly with CD28. A protein called CTLA-4 binds to the exact same B7-1 and B7-2 partners, but instead of activating the T cell, it dials the response down. CTLA-4 binds roughly 10 times more tightly than CD28 does, meaning that once CTLA-4 shows up on a T cell’s surface, it effectively outcompetes CD28 and shuts things down. This competition is how the body prevents immune responses from spiraling out of control.
Inhibitory signals through CTLA-4 are dominant over the activation signals through CD28. This balance is so important that disrupting it in either direction has dramatic consequences: too much CD28 signaling causes dangerous inflammation, while blocking it can suppress the immune system enough to allow transplanted organs to survive.
What Happens When CD28 Is Lost
At birth, virtually all human T cells carry CD28. That changes with age. By age 80 and beyond, roughly 10 to 15% of helper T cells and 50 to 60% of killer T cells have lost CD28 expression entirely. This loss is one of the most prominent features of immune aging.
T cells that have lost CD28 behave differently. They tend to be highly aggressive effector cells that are easily triggered by inflammation, yet the overall immune system becomes weaker because these cells accumulate at the expense of the naive T cells needed to fight new infections. This helps explain why older adults respond less effectively to vaccines and new pathogens.
Chronic inflammation accelerates the process. Elevated numbers of CD28-negative T cells appear in patients with rheumatoid arthritis, multiple sclerosis, Graves’ disease, and ankylosing spondylitis. These cells also show up in people at risk for inflammatory vascular events like plaque rupture, acute coronary syndrome, and stroke. It’s a striking paradox: the same cells that weaken the immune system’s ability to handle new threats also amplify autoimmune and inflammatory damage to tissues.
CD28 in Cancer Immunotherapy
CD28’s signaling properties have been engineered directly into one of the most important cancer treatments of the last decade: CAR-T cell therapy. In this approach, a patient’s T cells are removed, genetically modified to recognize cancer cells, and then infused back into the body. The internal signaling portion of these engineered T cells often includes a fragment of CD28 to boost their activation.
CAR-T cells built with a CD28 signaling domain expand rapidly and attack tumors aggressively, but they tend to exhaust quickly and don’t persist long in the body. An alternative design uses a different costimulatory molecule called 4-1BB, which produces slower expansion but better long-term survival of the engineered cells. Researchers have traced this tradeoff to a single amino acid in the CD28 domain that drives T cell exhaustion. Swapping that one residue reduced exhaustion and improved durable tumor control in lab models, pointing toward next-generation designs that combine the speed of CD28 with the staying power of 4-1BB.
Drugs That Target the CD28 Pathway
Because CD28 signaling is so central to T cell activation, blocking it can powerfully suppress immune responses. Two drugs do this by intercepting the B7 molecules before they reach CD28. Abatacept is used to treat rheumatoid arthritis and other autoimmune conditions. Belatacept, a higher-affinity version of the same concept, is used in kidney transplant recipients to prevent organ rejection. Both work by mimicking CTLA-4, binding B7-1 and B7-2 so tightly that CD28 can’t access them. In transplant patients, belatacept improved long-term graft function and was associated with fewer donor-specific antibodies compared to older immunosuppressive regimens.
However, blocking this pathway isn’t without complications. Because these drugs also prevent B7 molecules from reaching CTLA-4 (the natural brake), they can paradoxically increase the risk of rejection in some transplant patients, particularly with more intensive dosing.
The TGN1412 Disaster
The power of CD28 signaling was demonstrated in the most alarming way possible during a 2006 clinical trial in London. A drug called TGN1412 was designed as a “superagonist,” an antibody that could activate CD28 directly without requiring the T cell’s receptor to first recognize a target. The idea was to expand beneficial regulatory T cells, but the result was catastrophic.
Within 90 minutes of receiving a single intravenous dose, all six volunteers who got the drug developed a massive inflammatory response: headache, muscle pain, nausea, diarrhea, flushing, and dangerously low blood pressure. Within 12 to 16 hours, they became critically ill with lung injury, kidney failure, and widespread blood clotting. Their immune cells, flooded with inflammatory signals, were severely depleted within 24 hours. Investigators confirmed there was no manufacturing error, contamination, or dosing mistake. The drug did exactly what CD28 superagonism does in humans, something that preclinical animal studies had failed to predict.
The TGN1412 trial reshaped how first-in-human studies of immune-stimulating drugs are conducted and remains a stark illustration of how central CD28 is to immune activation. Stimulating it without restraint triggers the kind of runaway inflammatory cascade that the CTLA-4 braking system exists to prevent.