CTLA-4 (Aglyco-Fc-Fusion)

CTLA-4, also known as CD152, is structurally related to, and shares ligands (B7-1 and B7-2(CD86)) with CD28. CTLA-4 mediates negative signals that attenuate CD28-mediated positive signals. P7095G contains the IgV domain of human CTLA-4 fused with an aglycosylated mouse IgG2a Fc domain.

Interacting protein(s): B7-1 (CD80), B7-2 (CD86) (P7093F)
Related products: Checkpoint Proteins

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Quick Spec

Description

CTLA-4 and CD28 are structurally and functionally related, both bind to B7-1 and B7-2(CD86), and their genes are located in proximity suggesting a common evolutionary ancestor. CTLA-4 is particular conserved in evolution as human and mouse proteins share identical intracellular sequences. Like CD28, CTLA-4 also forms natural disulfide-linked dimers in the absence of ligand. Upon interacting with the apparent dimeric ligands, the receptor-ligand complexes exhibit as a unique alternating zipper like chain.

CTLA-4 binds to B7-2(CD86) and B7-1 with an affinity of 0.4 uM and 2.2 uM, respectively. CTLA-4 is expressed on the activated, but not resting, T lymphocytes which is peak at 24 hour after antigen presentation and subsided by 72 hours. The expression level of CTLA-4 is about 30-50 times lower than that of CD28, yet CTLA-4 exhibits a high affinity for bindings to their common ligands. The up-regulation of CTLA-4 is primarily post-transcriptional. Unlike CD28, ligation of CTLA-4 delivers inhibitory signals for T cell responses. Anti-CTLA-4 antibodies enhance T cell responses and CTLA-4 deficiency mice develop lymphoproliferative disorders.

Through the associated phosphatase, CTLA-4 was reported to be capable of attenuating the kinase activities transduced by T cell receptors. Genetic variations in CTLA-4 are associated with susceptibility to several autoimmune disorders, such as systemic lupus erythematosus (SLE), insulin-dependent diabetes mellitus (IDDM), celiac disease type 3 (CELIAC3). Engineered fusion proteins consisting of the extracellular domain of CTLA-4 and the IgG Fc region (CTLA-4-Ig), act as decoys for B7 ligands, hence block the CD28-meidated positive co-stimulatory signals and T-cell-dependent antibody responses. CTLA-4-Fc is used as immunosuppressive agents.

Amino Acid Sequence

References

1. Hossen MM, Ma Y, Yin Z, Xia Y, Du J, Huang JY, et al. Current understanding of CTLA-4: from mechanism to autoimmune diseases. Front Immunol. 2023;14:1198365. Epub 20230711. doi: 10.3389/fimmu.2023.1198365. PubMed PMID: 37497212; PubMed Central PMCID: PMC10367421.

2. CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. Harper K., Balzano C., Rouvier E., Mattei M.-G., Luciani M.-F., Golstein P. J. Immunol. 147:1037-1044 (1991)

3. Solution structure of human CTLA-4 and delineation of a CD80/CD86 binding site conserved in CD28. Metzler W.J., Bajorath J., Fenderson W., Shaw S.Y., Constantine K.L., Naemura J., Leytze G., Peach R.J., Lavoie T.B., Mueller L., Linsley P.S. Nat. Struct. Biol. 4:527-531 (1997)

4. Linsley, P.S., W. Brady, M. Urnes, L.S. Grosmaire, N.K. Damle, and J.A. Ledbetter. 1991. CTLA-4 is a second receptor for the B cell activation antigen B7. J. Exp. Med. 174:604-608 (2001)