CTLA-4

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CTLA-4
CTLA-4
Structure of the murine CTLA4 receptor (CD152)

Existing structural data : 1AH1 , 1H6E , 1I85 , 1I8L , 2X44 , 3BX7 , 3OSK

Properties of human protein
Mass / length primary structure 223 amino acids
Identifier
Gene names CTLA4 CD; CD152; CELIAC3; CTLA-4; GRD4; GSE; IDDM12
External IDs
Orthologue
human mouse
Entrez 1493 12477
Ensemble ENSG00000163599 ENSMUSG00000026011
UniProt P16410 P09793
Refseq (mRNA) NM_001037631 NM_009843
Refseq (protein) NP_001032720 NP_033973
Gene locus Chr 2: 204.73 - 204.74 Mb Chr 1: 60.89 - 60.92 Mb
PubMed search 1493 12477

CTLA-4 or CTLA4 (English for cytotoxic T-lymphocyte-associated protein 4 ), also known as CD152 (English for cluster of differentiation 152 ) is a protein that plays an important role in regulating the immune system . This protein CTLA-4 is specifically to the cell surface of T cells expresses that the immune response to antigens cited. T cells are stimulated by certain receptors (such as CD28 ), whereby an overreaction of the immune system is downregulated by CTLA-4 and thus prevented. This protein is encoded on chromosome 2 in humans.

Function and mode of operation

CTLA-4 is an important member of the immunoglobulin superfamily that is expressed on the surface of T helper cells , cytotoxic T cells, and also regulatory T cells. T cells themselves require two signals in order to become active, divide and differentiate. The first signal is antigen- dependent, while the second signal has a costimulatory effect and alone does not cause a reaction by the T cell. At the same time, however, activation of T lymphocytes by the T cell receptor leads to an increased production of the CTLA-4 receptor on the surface of the T cell. This receptor CTLA-4 transmits an inhibitory signal to avoid an overreaction of the immune system .

CTLA-4 has an antagonistic effect on the complex of the immunological synapse (CD80-CD86-CD28) and binds to CD80 / CD86, so that CD28 remains unbound. A protein kinase is activated via the CTLA-4 complex, which then downregulates the proliferation signal. As a result, antigen-presenting cells are less stimulated and the intensity of a possible immune response decreases.

structure

The CTLA-4 protein has an extracellular V-shaped domain and a transmembrane domain. CTLA-4 is also similar in structure to the co-stimulatory receptor CD28, with both receptors also binding to CD80 and CD86 (also known as B7-1 and B7-2). CD80 and CD86 are two proteins on the antigen presenting cells . When binding to CD80 or CD86, there is a competition between an inhibitory signal (from CTLA-4) and a co-stimulatory signal (from CD28).

Clinical significance

The protein CTLA-4 represents a possible clinical target to either increase the effect of CTLA-4 ( agonist ) or to weaken its effect ( antagonist ). The monoclonal antibody ipilimumab , for example, is an antagonist that binds to CTLA-4 and mitigates its action. In this way, it triggers anti-tumor effects in the early phase of T-cell activation and strengthens the immune system's fight against malignant melanomas . Ipilimumab was approved as the first checkpoint inhibitor in the USA in 2011 for the immunotherapy of metastatic melanoma. This was based on the data from a clinical study in metastatic melanoma, which demonstrated a significant survival advantage over standard therapy with a sustained tumor response rate of 10–15%. In contrast to this, the fusion protein abatacept tries to strengthen the effect of CTLA4 and thus successfully treat autoimmune diseases .

CTLA-4 deficiency

In the case of CTLA-4 deficiency, a rare congenital mutation in the CTLA4 gene can lead to an immunodeficiency and immune dysregulation syndrome. The inheritance is autosomal dominant, so the predisposition is inherited with a probability of 50%. However, there is a reduced penetrance and expressivity, which means that not all mutation carriers fall ill and the clinical picture of the symptomatic mutation carriers can vary in strength. This variability raises the question of the existence of possible modifying factors that may be genetic or environmental.

Clinical picture

The clinical picture of CTLA-4 deficiency is very variable and often consists of a symptom complex of antibody deficiency, recurrent respiratory infections, as well as autoimmunity, lymphocytic organ infiltration and enteropathies with diarrhea.

therapy

The therapy depends heavily on the symptoms of the individual patient. Frequently, the missing antibodies need to be replaced by regular infusions, and various immunosuppressive drugs are used to stabilize the immune system. Another possibility is the use of the drug abatacept, which can at least partially replace the function of the body's missing CTLA-4.

Individual evidence

  1. a b c McCoy Kathy: The role of CTLA-4 in the regulation of T cell immune responses . In: Immunology and Cell Biology . 77, 1999, pp. 1-10. doi : 10.1046 / j.1440-1711.1999.00795.x .
  2. a b c Sansom D .: CD28, CTLA-4 and their ligands: who does what and to whom? . In: Immunology . 101, 2000, pp. 169-177. doi : 10.1046 / j.1365-2567.2000.00121.x .
  3. ML Baroja, L. Vijayakrishnan, E. Bettelli, PJ Darlington, TA Chau, V. Ling, M. Collins, BM Carreno, J. Madrenas, VK Kuchroo: Inhibition of CTLA-4 function by the regulatory subunit of serine / threonine phosphatase 2A. In: Journal of Immunology (Baltimore, Md .: 1950). Volume 168, Number 10, May 2002, pp. 5070-5078, ISSN  0022-1767 . PMID 11994459 , doi: 10.4049 / jimmunol.168.10.5070 .
  4. ^ Krummel MF: CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation . In: J Exp Med . . 182, 1995, pp. 459-465. PMID 7543139 .
  5. Hodi FS, O'Day SJ, McDermott DF et al. (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363: 711-723
  6. Summary of Product Characteristics. (PDF) EMA, accessed on August 4, 2014 (English).