title: Identification of residues in the V domain of CD80 (B7-1) implicated in functional interactions with CD28 and CTLA4.
abstract: The CD80 (B7-1) molecule is a 45-60-kD member of the immunoglobulin superfamily that is expressed on a variety of cell types of haematopoietic origin. CD80 can provide a critical costimulatory signal to T cells by interacting with the T cell surface molecule CD28. CD80 also binds to the CD28-related molecule CTLA4, which is expressed on activated T cells, Recently, additional ligands of CD28 and CTLA4 have been described in mice and humans. One of them, CD86 (B-70 or B7-2) was characterized at the molecular level. Although similar in predicted structure to CD80, it is distantly related in amino acid sequence. In this study, human CD80 mutants were generated and tested for their ability to maintain the interaction with CD28 leading to adhesion and enhanced IL-2 production. Two hydrophobic residues in the V-like domain of CD80 were identified as critical for binding to CD28 and are also important for the interaction with CTLA4. These residues are adjacent to the epitope of the BB1 antibody, which inhibits CD28-CD80 interactions. One of these residues, Y87, is conserved in all CD80 and CD86 cloned from various species. These results being to unravel the structural requirements for binding to CD28 and CTLA4.
authors.affiliation: Laboratoire d'Immunologie, Institut de Recherches Cliniques de Montréal, Québec, Canada.
authors.forename: C A
authors.initials: CA
authors.lastname: Fargeas
authors.forename: A
authors.initials: A
authors.lastname: Truneh
authors.forename: M
authors.initials: M
authors.lastname: Reddy
authors.forename: M
authors.initials: M
authors.lastname: Hurle
authors.forename: R
authors.initials: R
authors.lastname: Sweet
authors.forename: R P
authors.initials: RP
authors.lastname: Sékaly
mesh_terms: D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism*; D018122:B7-1 Antigen / Q000737:chemistry* / Q000378:metabolism*; D001483:Base Sequence; D018106:CD28 Antigens / Q000378:metabolism*; D060908:CTLA-4 Antigen; D006801:Humans; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000502:physiology; D014443:Tyrosine / Q000502:physiology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007376:Interleukin-2; D014443:Tyrosine; D000069594:Abatacept; D014364:Tryptophan