CTLA4 Gene

The CTLA4 gene (CTLA4 stands for "Cytotoxic T-Lymphocyte Associated Protein 4") is a protein-coding gene located on chromosome 2q33.2.

The gene encoded by CTLA4 encodes the receptor protein CTLA-4 (cytotoxic T lymphocyte antigen 4), also known as CD152 (cluster of differentiation 152) which transmits an inhibitory signal to T cells. This inhibitory receptor functions as an important negative regulator of T cell responses. CTLA4 is a member of the immunoglobulin superfamily expressed on the surface of T helper cells. Several transcriptional splice variants encoding different isoforms have been characterized. The membrane-bound isoform functions as a homodimer linked by a disulfide bond, while the soluble isoform functions as a monomer.

The receptor protein itself contains a V-domain, a transmembrane domain, and a cytoplasmic tail.

CTLA4 resembles the co-stimulatory T-cell protein CD28, and both molecules bind to its natural B7 family ligands CD80 and CD86, which are expressed on antigen-presenting cells. Binding of CTLA4 to CD80/ CD86 leads to a dramatic reduction in T cell activation.

In contrast, the interaction between CD28 and CD80/86 enhances T cell receptor (TCR) signaling. This leads to activation of T cells. However, CTLA-4 has a much higher overall affinity for CD80/86. Intracellular CTLA4 is also found in regulatory T cells and appears to be important for their function. Blockade of CTLA4 compensatorily leads to increased interaction between CD28 and CD80/86

• Mutations in the CTLA4 gene have been associated with insulin-dependent diabetes mellitus, Graves' disease, Behҫet's disease, Hashimoto's thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, autoimmunologic lymphoproliferative syndrome, type V (OMIM: 616100), and other autoimmune diseases (Kailashiya V et al. 2019; Kuehn HS et al. 2014; Park KS et al. 2009; Lopez-Nevado M et al. 2021).
• The biologic "Abatacept", a fusion protein of the Fc portion of human IgG1 and the extracellular domain of human CTLA4, is used in the therapy of rheumatoid arthritis. Through the CTLA4 domain, Abatacept can bind to CD80 and CD86 of antigen-presenting cells (APCs) and thus prevent costimulation of the T cell by an antigen-presenting cell.

1. Kailashiya V et al (2019) Role of CTLA4 A49G polymorphism in systemic lupus erythematosus and its geographical distribution. J Clin Pathol 72:659-662.
2. Kuehn HS et al (2014) Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 345: 1623-1627.
3. Lopez-Nevado M et al. (2021) Primary immune regulatory disorders with an autoimmune lymphoproliferative syndrome-like phenotype: immunologic evaluation, early diagnosis and management. Front. Immun. 12: 671755.
4. Park KS et al (2009) CTLA4 gene polymorphisms and soluble CTLA4 protein in Behcet's disease. Tissue Antigens 74:222-227.
5. Schubert D et al (2014) Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nature Med. 20: 1410-1416.
6. Schwab C et al. (2018) Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immun 142: 1932-1946.