CD28 protein is a disulfide linked-homodimer containing a single IgV domain is its extracellular portion. CD28 binds to CD80 and CD86 with low affinities and leads to positive signalling. P7090F contains human CD28 ECD fused with a mouse IgG2a Fc domain.
Interacting protein(s): B7-1 (CD80), B7-2 (CD86) (P7093F)
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|Tag:||Mouse IgG2a Fc|
|Construction:||Human CD28 (G18-P152)-mouse IgG2a Fc|
|MW (calculated):||42,319 daltons|
|MW (SDS-PAGE):||45 Kd|
|Abs 0.1% (= 1 mg/ml):||1.171|
CD28 has a single extracellular IgSF V-like domain and expressed as disulfide linked homodimers. CD28 shares with CTLA-4 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. CD28 is the only B7 receptor constitutively expressed on naive T cells. CD28 is a low affinity binding receptor for both B7.1 and B7.2 as compared with CTLA-4. However both &.1 and B7.2 interact with CD28 with similar equilibrium binding properties.
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. CD28 contains two intracellular motifs that are important for its signalling. The first is the YMNM motif, starting at Tyr170, which is critical for induction of Bcl-xL, up-regulation of transcription and protein production of IL-2, and NFkB activation. The second is a pair of pro-rich motifs. The N-terminus of these motifs binds to Itk and Tec that is critical for recruiting phosphorylated SH2-containing proteins to CD28. The C-terminus of these motifs is critical for bring Lck and lipid rafts into the immune synapse. Antigen activation of the TCR of a naive T cell without CD28:B7 interaction results in a T cell that is anergic.
CD28 has also been found to stimulate eosinophil granulocytes where the cytokine storm can be triggered by ligation of the surface CD28 and is likely the culprit of the complications associated with the development of TGN1412, an anti-CD28 drug candidate.
Amino Acid Sequence
1. Linsley PS, Ledbetter J, Peach R, Bajorath J. (1995) CD28/CTLA-4 receptor structure, binding stoichiometry and aggregation during T-cell activation. Res Immunol. 146:130-140.
2. Peach RJ, Bajorath J, Brady W, Leytze G, Greene J, Naemura J, Linsley PS. (1994) Complementarity determining region 1 (CDR1)- and CDR3-analogous regions in CTLA-4 and CD28 determine the binding to B7-1. J Exp Med. 180:2049-2058.
3. 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
4. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N. (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018-1028.