Interactions of CD80 and CD86 with CD28 and CTLA4.
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.
Ellis
J H
JH
Immunopathology Unit, Glaxo-Wellcome Medicines Research Centre, Hertfordshire, United Kingdom.
Burden
M N
MN
Vinogradov
D V
DV
Linge
C
C
Crowe
J S
JS
D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000737:chemistry / Q000378:metabolism*; D018122:B7-1 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051940:B7-2 Antigen; D001483:Base Sequence; D001667:Binding, Competitive / Q000276:immunology; D018106:CD28 Antigens / Q000737:chemistry / Q000378:metabolism*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D017124:Conserved Sequence / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry; D006801:Humans; D018796:Immunoconjugates; D008024:Ligands; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D051381:Rats; D015398:Signal Transduction / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C497966:Cd86 protein, rat; C556708:Ctla4 protein, rat; D000939:Epitopes; D018796:Immunoconjugates; D008024:Ligands; D008562:Membrane Glycoproteins; D010455:Peptides; D000069594:Abatacept