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. P095F contains the IgV domain of human CTLA-4 fused with a mouse IgG2a Fc domain.
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|Synonym:||CD152, CELIAC3, GRD4, GSE, IDDM12|
|Tag:||Mouse IgG2a Fc|
|Construction:||Human CTLA-4 (A37-D161)-mouse IgG2a Fc|
|MW (calculated):||40493 Kd|
|MW (SDS-PAGE):||43 Kd|
|Abs 0.1% (= 1 mg/ml):||1.077|
Just like CD28, CTLA-4 has a single extracellular IgSF V-like domain and expressed as disulfide linked homodimers. CTLA-4 shares with CD28 a hexapeptide MYPPPY motif which maps to the CDR3-like loop region. These residues are important binding of B7.1 and B7.2 since mutations in this loop reduce binding activity of CTLA-4 as well. In contrast to CD28 which is constitutively expressed on naive T cells, CTLA-4 is induced 24-48 hours after T cell activation via phosphorylation by a number of kinases which prompts the its translocation to the surface.
CLTA-4 is a higher affinity binding receptor for both B7.1 and B7.2 as compared with CD28. Surface plasmon resonance experiment showed that both CD28 and CTLA-4 have a very fast off-rate of binding to B7.1 and B7.2. The higher avidity of CTLA-4 binding is primarily due to it very fast on-rate. In contrast to the positive signal triggered by CD28:B7 protein interactions, the engagement of CTLA-4 with these ligands provides a negative regulation of the immune response. This is also shown by CTLA-4 deficient mice showed lympho-proliferative disorders that lead to neonatal death underscoring the central role of this receptor in induction of peripheral tolerance.
At least part of the CTLA-4’s negative regulatory activity may result from its ability to enhance the generation of Treg cells and/or modulation of their functions as the CTLA-4 blockade caused the abrogation of Treg functions in vivo. An anti-CTLA-4 antibody, MDX-100 which blocks the interaction of CTLA-4 with B7.1 an dB7.2 and leads to direct activation of effector T cells and/or depletion of the Treg cells, has been approved for treatment of advanced melanoma.
Amino Acid Sequence
1. Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R. (1994) Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity. 1:793-801.
2. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S. (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science. 322:271-275
3. Read S, Greenwald R, Izcue A, Robinson N, Mandelbrot D, Francisco L, Sharpe AH, Powrie F. (2006) Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J Immunol. 177:4376-4383.
4. Maker AV, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Hughes M, Yellin MJ, Haworth LR, Levy C, Allen T, Mavroukakis SA, Attia P, Rosenberg SA. (2006) Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother. 29:455-4563.