CTLA-4

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Structure of murine CTLA4 (CD152)
CTLA4 molecule
Identifiers
Symbol	CD152
HUGO	2505
Entrez	1493
OMIM	123890
UniProt	P10747
PDB	1DQT
Other data
Locus	Chr. 2 q33

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.

CTLA-4 is another CD28 family receptor, but in contrast to the rest of the family it negatively regulates the activation of T cells. 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.

The comparatively higher binding affinity of CTLA4 has made it a potential therapy for autoimmune diseases. Fusion proteins of CTLA4 and antibodies (CTLA4-Ig) have been used in clinical trials for rheumatoid arthritis[1]. 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.