title: Expression and functional significance of an additional ligand for CTLA-4.
abstract: Effective T-cell activation requires antigen/major histocompatibility complex engagement by the T-cell receptor complex in concert with one or more costimulatory molecules. Recent studies have suggested that the B7 molecule, expressed on most antigen presenting cells, functions as a costimulatory molecule through its interaction with CD28 on T cells. Blocking the CD28/B7 interaction with CTLA4Ig inhibits T-cell activation in vitro and induces unresponsiveness. We demonstrate that another molecule(s), termed B7-2, is expressed constitutively on dendritic cells, is differentially regulated on B cells, and costimulates naive T cells responding to alloantigen. B7-2 is up-regulated by lipopolysaccharide in < 6 hr and is maximally expressed on the majority of B cells by 24 hr. In contrast, B7 is detected only on a subset of activated B cells late (48 hr) after stimulation. In addition, Con A directly induces B7-2 but not B7 expression on B cells. Finally, although both anti-B7 monoclonal antibodies and CTLA4Ig blocked T-cell proliferation to antigen-expressing B7 transfectants, only CTLA4Ig had any significant inhibitory effect on T-cell proliferation to antigens expressed on natural antigen presenting cells, such as dendritic cells. Thus, B7 is not the only costimulatory molecule capable of initiating T-cell responses since a second ligand, B7-2, can provide a necessary second signal for T-cell activation.
authors.affiliation: Roche Research Center, Nutley, NJ 07110.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lenschow
authors.forename: G H
authors.initials: GH
authors.lastname: Su
authors.forename: L A
authors.initials: LA
authors.lastname: Zuckerman
authors.forename: N
authors.initials: N
authors.lastname: Nabavi
authors.forename: C L
authors.initials: CL
authors.lastname: Jellis
authors.forename: G S
authors.initials: GS
authors.lastname: Gray
authors.forename: J
authors.initials: J
authors.lastname: Miller
authors.forename: J A
authors.initials: JA
authors.lastname: Bluestone
mesh_terms: D000069594:Abatacept; D000818:Animals; D000915:Antibody Affinity; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism*; D051940:B7-2 Antigen; D001483:Base Sequence; D060908:CTLA-4 Antigen; D017931:DNA Primers / Q000737:chemistry; D003713:Dendritic Cells / Q000276:immunology; D018796:Immunoconjugates; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D017931:DNA Primers; D018796:Immunoconjugates; D008024:Ligands; D008562:Membrane Glycoproteins; D000069594:Abatacept