CTLA4, also named as CD152, is a protein receptor that acts as an immune checkpoint, downregulating immune responses. Expressed in regulatory T cells, but only unregulated in conventional T cells after activation. When bound to antigen-presenting cells, it acts as an off switch. Discovered in 1987, CTLA4 was identified by Pierre Golstein and his team. In 1995, Arlene H Sharpe published their findings detailing the fact that CTLA4 acts as a negative regulator of T-cell activation.
The clinical significance of CTLA4 is the fact that variations of this gene have been associated with insulin-dependent diabetes, Graves’ disease, thyroid, celiac disease, systematic lupus, and other autoimmune diseases. Different forms of the CTLA4 gene are associated with these autoimmune diseases, although this association is usually weak. In conditions like Lupus, the variant of CTLA4 is found to be produced in the serum of active systemic lupus patients. The symptoms of these conditions and other autoimmune diseases are inherited in an autosomal dominant manner, which means that just one abnormal gene from one parent is required.
A member of the immunoglobulin superfamily, CTLA4 is activated by T cells and sends signals to them that inhibit their activation. CTLA4 is similar to the T-cell co-stimulatory protein, CD28, with both of these binding to CD80 and CD86. CTLA4 transmits an inhibitory signal to T cells, while CD28 sends a stimulatory signal. Found in regulatory cells, CTLA4 also contributes to its inhibitory function.
The structure of CTLA4 is a protein that contains an extracellular V domain, a transmembrane, and a cytoplasmic tail. Membrane-bound, the isoform functions as a homodimer which is connected by a disulfide bond, with the soluble isoform acting as a monomer. The domain of the cell is like that of CD28, because it too has no intrinsic catalytic activity, and also contains YVKM motif which can bind P13K, PP2A, and SHP2. The first step of CTLA4 in stopping T cell responses is via SHP2 and PP2A, using signalling proteins like CD3 and LAT. CTLA4 can also impact signalling via competing with CD28 for the binding from CD80 and CD86.
The mechanism within which CTLA4 acts in T cells still remains controversial, with a range of different options around this topic. Biochemical evidence suggests that CTLA4 recruits a phosphatase to the T cell receptor, reducing the force of the signal. This theory is unconfirmed, however. More recently, it has been suggested that CTLA4 may function in vivo by removing B7-1 and B7-2 from the membranes of antigen cells, stopping them from triggering CD28.
The higher binding affinity of CTLA4 has made it a potential therapy for autoimmune disease patients, with fusion proteins of CTLA4 already having been used in trials to treat rheumatoid arthritis. There is also increased interest in the potential possibility that blocking CTLA4 could be used to inhibit the immune system’s tolerance to tumors and treatments by providing an immunotherapy strategy for patients with cancer. This is the first approved immune checkpoint therapy - there are many others coming, these just haven’t been approved yet for human use.