CTLA-4

Cytotoxic T-lymphocyte-associated protein 4
Structure of murine CTLA4 (CD152)
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1AH1, 1H6E, 1I85, 1I8L, 2X44, 3BX7, 3OSK
Identifiers
Symbols	CTLA4 ; ALPS5; CD; CD152; CELIAC3; CTLA-4; GRD4; GSE; IDDM12
External IDs	OMIM: 123890 MGI: 88556 HomoloGene: 3820 GeneCards: CTLA4 Gene
Gene ontology Molecular function • protein binding Cellular component • Golgi apparatus • plasma membrane • integral component of plasma membrane • external side of plasma membrane • clathrin-coated endocytic vesicle • perinuclear region of cytoplasm Biological process • adaptive immune response • immune response • cellular response to DNA damage stimulus • negative regulation of B cell proliferation • T cell costimulation • positive regulation of apoptotic process • negative regulation of regulatory T cell differentiation • B cell receptor signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1493	12477
Ensembl	ENSG00000163599	ENSMUSG00000026011
UniProt	P16410	P09793
RefSeq (mRNA)	NM_001037631	NM_001281976
RefSeq (protein)	NP_001032720	NP_001268905
Location (UCSC)	Chr 2: 203.87 – 203.87 Mb	Chr 1: 60.89 – 60.92 Mb
PubMed search	[1]	[2]

CTLA4 or CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 (cluster of differentiation 152), is a protein receptor that, functioning as an immune checkpoint, downregulates the immune system. CTLA4 is found on the surface of T cells, and acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells.

The CTLA-4 protein is encoded by the Ctla4 gene in mice and the CTLA4 gene in humans.

Function

CTLA4 is a member of the immunoglobulin superfamily that is expressed on the surface of Helper T cells and transmits an inhibitory signal to T cells. CTLA4 is similar to the T-cell co-stimulatory protein, CD28, and both molecules bind to CD80 and CD86, also called B7-1 and B7-2 respectively, on antigen-presenting cells. CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. 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.

The mechanism by which CTLA-4 acts in T cells remains somewhat controversial. Biochemical evidence suggested that CTLA-4 recruited a phosphatase to the T cell receptor, thus attenuating the signal. This work remains unconfirmed in the literature since its first publication. More recent work has suggested that CTLA-4 may function in vivo by capturing and removing B7-1 and B7-2 from the membranes of antigen-presenting cells, thus making these unavailable for triggering of CD28.

CTLA-4 may also function via modulation of cell motility and/or signaling through PI3 kinase Early multiphoton microscopy studies observing T-cell motility in intact lymph nodes appeared to give evidence for the so-called ‘reverse-stop signaling model’. In this model CTLA 4 reverses the TCR-induced ‘stop signal’ needed for firm contact between T cells and antigen-presenting cells (APCs). However, those studies compared CTLA-4 positive cells, which are predominantly regulatory cells and are at least partially activated, with CTLA-4 negative naive T cells. The disparity of these cells in multiple regards may explain some of these results. Other groups who have analyzed the effect of antibodies to CTLA-4 in vivo have concluded little or no effect upon motility. Antibodies to CTLA-4 may exert additional effects when used in vivo, by binding and thereby depleting regulatory T cells.

Structure

The protein contains an extracellular V domain, a transmembrane domain, and a cytoplasmic tail. Alternate splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. The intracellular domain is similar to that of CD28, in that it has no intrinsic 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

Mutations in this gene have been associated with insulin-dependent diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, primary biliary cirrhosis and other autoimmune diseases.

Polymorphisms of the CTLA-4 gene are associated with autoimmune diseases such as autoimmune thyroid disease and multiple sclerosis, though this association is often weak. In Systemic Lupus Erythematosus (SLE), the splice variant sCTLA-4 is found to be aberrantly produced and found in the serum of patients with active SLE.

Germline haploinsufficiency

Germline haploinsufficiency of CTLA4 leads to CTLA4 deficiency or CHAI disease (CTLA4 haploinsufficiency with autoimmune infiltration), a rare genetic disorder of the immune system. This may cause a dysregulation of the immune system and may result in lymphoproliferation, autoimmunity, hypogammaglobulinemia, recurrent infections, and may slightly increase one’s risk of lymphoma. CTLA4 mutations have first been described by a collaboration between the groups of Dr. Gulbu Uzel, Dr. Steven Holland, and Dr. Michael Lenardo from the National Institute of Allergy and Infectious Disease, Dr. Thomas Fleisher from the NIH Clinical Center at the National Institutes of Health, and their collaborators in 2014. In the same year a collaboration between the groups of Dr. Bodo Grimbacher, Dr. Shimon Sakaguchi, Dr. Lucy Walker and Dr. David Sansom and their collaborators described a similar phenotype.

CTLA4 mutations are inherited in an autosomal dominant manner. This means a person only needs one abnormal gene from one parent. The one normal copy is not enough to compensate for the one abnormal copy. Dominant inheritance means most families with CTLA4 mutations have affected relatives in each generation on the side of the family with the mutation.

Clinical and laboratory manifestations

Symptomatic patients with CTLA4 mutations are characterized by an immune dysregulation syndrome including extensive T cell infiltration in a number of organs, including the gut, lungs, bone marrow, central nervous system, and kidneys. Most patients have diarrhea or enteropathy. Lymphadenopathy and hepatosplenomegaly are also common, as is autoimmunity. The organs affected by autoimmunity vary but include thrombocytopenia, hemolytic anemia, thyroiditis, psoriasis, and arthritis. Respiratory infections are also common. Importantly, the clinical presentations and disease courses are variable with some individuals severely affected, whereas others show little manifestation of disease. This “variable expressivity,” even within the same family, can be striking and may be explained by differences in lifestyle, exposure to pathogens, treatment efficacy, or other genetic modifiers.

The clinical symptoms are caused by abnormalities of the immune system. Most patients develop reduced levels of at least one immunoglobulin isotype, and have low CTLA4 protein expression in T regulatory cells, hyperactivation of effector T cells, low switched memory B cells, and progressive loss of circulating B cells.

Treatment

Once a diagnosis is made, the treatment is based on an individual’s clinical condition and may include standard management for autoimmunity and immunoglobulin deficiencies. Additionally, treatment with the CTLA4 mimetic, CTLA4-Ig, which reduces immune activity, may be a potential therapeutic intervention.

Agonists to reduce immune activity

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 PD-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 was recently approved by the FDA based on favorable results from the randomized Phase III BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First Line Immunosuppression) study. It was approved for renal transplantation in patients that are sensitized to Epstein–Barr virus (EBV).

Antagonists to increase immune activity

Conversely, there is increasing interest in the possible therapeutic benefits of blocking CTLA4 (using antagonistic antibodies against CTLA such as ipilimumab (FDA approved for melanoma in 2011) as a means of inhibiting immune system tolerance to tumours and thereby providing a potentially useful immunotherapy strategy for patients with cancer. This is the first approved immune checkpoint blockade therapy.

Interactions

CTLA-4 has been shown to interact with:

• AP2M1,
• CD80,
• CD86,
• SHP-2, and
• PPP2R5A.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.