CTLA-4 is a second receptor for the B cell activation antigen B7.
Functional interactions between T and B lymphocytes are necessary for optimal activation of an immune response. Recently, the T lymphocyte receptor CD28 was shown to bind the B7 counter-receptor on activated B lymphocytes, and subsequently to costimulate interleukin 2 production and T cell proliferation. CTLA-4 is a predicted membrane receptor from cytotoxic T cells that is homologous to CD28 and whose gene maps to the same chromosomal band as the gene for CD28. It is not known, however, if CD28 and CTLA-4 also share functional properties. To investigate functional properties of CTLA-4, we have produced a soluble genetic fusion between the extracellular domain of CTLA-4 and an immunoglobulin C gamma chain. Here, we show that the fusion protein encoded by this construct, CTLA4Ig, bound specifically to B7-transfected Chinese hamster ovary cells and to lymphoblastoid cells. CTLA4Ig also immunoprecipitated B7 from cell surface 125I-labeled extracts of these cells. The avidity of 125I-labeled B7Ig fusion protein for immobilized CTLA4Ig was estimated (Kd approximately 12 nM). Finally, we show that CTLA4Ig was a potent inhibitor of in vitro immune responses dependent upon cellular interactions between T and B lymphocytes. These findings provide direct evidence that, like its structural homologue CD28, CTLA-4 is able to bind the B7 counter-receptor on activated B cells. Lymphocyte interactions involving the B7 counter-receptor are functionally important for alloantigen responses in vitro.
Linsley
P S
PS
Oncogen Division, Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121.
Brady
W
W
Urnes
M
M
Grosmaire
L S
LS
Damle
N K
NK
Ledbetter
J A
JA
D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D000954:Antigens, Surface / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology*; D018122:B7-1 Antigen; D001483:Base Sequence; D060908:CTLA-4 Antigen; D002460:Cell Line; D018796:Immunoconjugates; D066298:In Vitro Techniques; D008024:Ligands; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry; D011233:Precipitin Tests; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000954:Antigens, Surface; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D008024:Ligands; D009841:Oligonucleotides; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D000069594:Abatacept