Interactions of CD80 and CD86 with CD28 and CTLA4.

Abstract

CD80 and CD86 are cell surface glycoproteins expressed on a variety of professional APCs. They have attracted much attention due to their function as potent costimulators of T lymphocyte function through their interaction with CD28 and possibly CTLA4. Because inhibitors of this interaction may have therapeutic relevance in human autoimmune disease, we investigated the properties of linear peptides derived from conserved regions of CTLA4 and CD80 known to be essential for binding. None of these peptides were sufficient to bind ligand, nor did they act as potent competitive inhibitors. Conformationally constrained versions of the CTLA4 motif were also inactive. These results suggested that other parts of the proteins are important in determining binding, so a series of modified CD80 and CD86 molecules were constructed in an attempt to identify other binding determinants. Insertion of two residues between the two Ig domains of CD80 resulted in decreased affinity for CTLA4, but a similar mutation in CD86 was without effect. We also identified another asymmetry between CD80 and CD86 in that the V domain of CD86 but not that of CD80 is sufficient for CTLA4 binding. The CD86-V domain appears to have CTLA4 binding properties equivalent to that of intact CD86. These data illustrate a fundamental difference between these costimulatory molecules and suggest a mechanism by which they may be differentially recognized by receptors on the T cell surface.

Costimulatory Blockade by CD28 Peptide Mimics: Suppression of Experimental Autoimmune Encephalomyelitis

“…The importance o f the polyproline m otif in the CDR-3 like region of CD 28 for binding B7 ligands is well documented by mutagenesis (167,169). However, the results o f a previous study and our observations have shown that a synthetic peptide consisting o f the "M YPPPY' m otif alone does not constitute a minimal ligand binding epitope (178). In general, a "functional epitope" defined by mutagenesis is much smaller that the "structural epitope" seen in the three-dimensional structures.…”

The Inhibitor of Costimulation of T Cells: Abatacept

“…CD28 signaling is triggered by its counter receptors CD80/CD86 [expressed on antigen-presenting cells (APC)] and is regulated by a physiological antagonist (cytotoxic T lymphocyte antigen-4, CD152; CTLA4) expressed by T cells. CTLA4 binds to CD80/86 with high avidity and prevents T cell activation by blocking intracellular CD28 downstream events 4 . The inhibition of CD28-driven costimulation can be the ideal target to downregulate T cell activity in Th1-mediated diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA).…”