CTLA-4

CTLA4 (Cytotoxic T-Lymphocyte Antigen 4) is a CD28-family receptor expressed on mainly CD4+ T cells. It binds the same ligands as CD28 (CD80 and CD86 on B cells and dendritic cells), but with higher affinity than CD28. However, in contrast to CD28 which enhances cell function when bound at the same time as the T cell receptor, CTLA4 inhbits the T cell and prevents it from functioning. Intracellular CTLA4 is also found in regulatory T cells and may be important to their function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4, an inhibitory receptor for B7 molecules (i.e. CD80 and CD 86).

The intracellular domain is similar to that of CD28, in that it has no intrinisic catalytic activity and contains one YVKM motif able to bind PI3K, PP2A and SHP-2 and one proline-rich motif able to bind SH3 containing proteins. The first role of CTLA-4 in inhibiting T cell responses seem to be directly via SHP-2 and PP2A dephosphorylation of TCR-proximal signalling proteins such as CD3 and LAT. CTLA-4 can also affect signalling indirectly via competing with CD28 for CD80/86 binding. CTLA-4 can also bind PI3K, although the importance and results of this interaction are uncertain.

Clinical significance
The comparatively higher binding affinity of CTLA4 has made it a potential therapy for autoimmune diseases. It plays a role in the initial immune response to and infection of immune cells by HIV, along with the CD-1 pathway and others. Fusion proteins of CTLA4 and antibodies (CTLA4-Ig) have been used in clinical trials for rheumatoid arthritis. The fusion protein CTLA4-Ig is commercially available as Orencia (abatacept). A second generation form of CTLA4-Ig known as belatacept is currently being tested in trials. Both of these compounds are expected to find wide use in organ transplantation.