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J Exp Med. Sep 1, 1991; 174(3): 561–569.
PMCID: PMC2118936

CTLA-4 is a second receptor for the B cell activation antigen B7

Abstract

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Janeway CA., Jr Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 1):1–13. [PubMed]
  • Bretscher P, Cohn M. A theory of self-nonself discrimination. Science. 1970 Sep 11;169(3950):1042–1049. [PubMed]
  • Weiss A. Structure and function of the T cell antigen receptor. J Clin Invest. 1990 Oct;86(4):1015–1022. [PMC free article] [PubMed]
  • Schwartz RH. A cell culture model for T lymphocyte clonal anergy. Science. 1990 Jun 15;248(4961):1349–1356. [PubMed]
  • Springer TA. Adhesion receptors of the immune system. Nature. 1990 Aug 2;346(6283):425–434. [PubMed]
  • June CH, Ledbetter JA, Linsley PS, Thompson CB. Role of the CD28 receptor in T-cell activation. Immunol Today. 1990 Jun;11(6):211–216. [PubMed]
  • Thompson CB, Lindsten T, Ledbetter JA, Kunkel SL, Young HA, Emerson SG, Leiden JM, June CH. CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1333–1337. [PMC free article] [PubMed]
  • Lindstein T, June CH, Ledbetter JA, Stella G, Thompson CB. Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. Science. 1989 Apr 21;244(4902):339–343. [PubMed]
  • Fraser JD, Irving BA, Crabtree GR, Weiss A. Regulation of interleukin-2 gene enhancer activity by the T cell accessory molecule CD28. Science. 1991 Jan 18;251(4991):313–316. [PubMed]
  • Linsley PS, Clark EA, Ledbetter JA. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5031–5035. [PMC free article] [PubMed]
  • Linsley PS, Brady W, Grosmaire L, Aruffo A, Damle NK, Ledbetter JA. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med. 1991 Mar 1;173(3):721–730. [PMC free article] [PubMed]
  • Damle NK, Linsley PS, Ledbetter JA. Direct helper T cell-induced B cell differentiation involves interaction between T cell antigen CD28 and B cell activation antigen B7. Eur J Immunol. 1991 May;21(5):1277–1282. [PubMed]
  • Kohno K, Shibata Y, Matsuo Y, Minowada J. CD28 molecule as a receptor-like function for accessory signals in cell-mediated augmentation of IL-2 production. Cell Immunol. 1990 Nov;131(1):1–10. [PubMed]
  • Aruffo A, Seed B. Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8573–8577. [PMC free article] [PubMed]
  • Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P. A new member of the immunoglobulin superfamily--CTLA-4. Nature. 1987 Jul 16;328(6127):267–270. [PubMed]
  • Brunet JF, Denizot F, Golstein P. A differential molecular biology search for genes preferentially expressed in functional T lymphocytes: the CTLA genes. Immunol Rev. 1988 Mar;103:21–36. [PubMed]
  • Dariavach P, Mattéi MG, Golstein P, Lefranc MP. Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains. Eur J Immunol. 1988 Dec;18(12):1901–1905. [PubMed]
  • Lafage-Pochitaloff M, Costello R, Couez D, Simonetti J, Mannoni P, Mawas C, Olive D. Human CD28 and CTLA-4 Ig superfamily genes are located on chromosome 2 at bands q33-q34. Immunogenetics. 1990;31(3):198–201. [PubMed]
  • Ledbetter JA, June CH, Grosmaire LS, Rabinovitch PS. Crosslinking of surface antigens causes mobilization of intracellular ionized calcium in T lymphocytes. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1384–1388. [PMC free article] [PubMed]
  • Ledbetter JA, Imboden JB, Schieven GL, Grosmaire LS, Rabinovitch PS, Lindsten T, Thompson CB, June CH. CD28 ligation in T-cell activation: evidence for two signal transduction pathways. Blood. 1990 Apr 1;75(7):1531–1539. [PubMed]
  • Yokochi T, Holly RD, Clark EA. B lymphoblast antigen (BB-1) expressed on Epstein-Barr virus-activated B cell blasts, B lymphoblastoid cell lines, and Burkitt's lymphomas. J Immunol. 1982 Feb;128(2):823–827. [PubMed]
  • Aruffo A, Seed B. Molecular cloning of two CD7 (T-cell leukemia antigen) cDNAs by a COS cell expression system. EMBO J. 1987 Nov;6(11):3313–3316. [PMC free article] [PubMed]
  • Saiki RK, Scharf S, Faloona F, Mullis KB, Horn GT, Erlich HA, Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. [PubMed]
  • Freeman GJ, Freedman AS, Segil JM, Lee G, Whitman JF, Nadler LM. B7, a new member of the Ig superfamily with unique expression on activated and neoplastic B cells. J Immunol. 1989 Oct 15;143(8):2714–2722. [PubMed]
  • Malik N, Kallestad JC, Gunderson NL, Austin SD, Neubauer MG, Ochs V, Marquardt H, Zarling JM, Shoyab M, Wei CM, et al. Molecular cloning, sequence analysis, and functional expression of a novel growth regulator, oncostatin M. Mol Cell Biol. 1989 Jul;9(7):2847–2853. [PMC free article] [PubMed]
  • Gross JA, St John T, Allison JP. The murine homologue of the T lymphocyte antigen CD28. Molecular cloning and cell surface expression. J Immunol. 1990 Apr 15;144(8):3201–3210. [PubMed]
  • Lee KP, Taylor C, Petryniak B, Turka LA, June CH, Thompson CB. The genomic organization of the CD28 gene. Implications for the regulation of CD28 mRNA expression and heterogeneity. J Immunol. 1990 Jul 1;145(1):344–352. [PubMed]
  • Damle NK, Doyle LV, Grosmaire LS, Ledbetter JA. Differential regulatory signals delivered by antibody binding to the CD28 (Tp44) molecule during the activation of human T lymphocytes. J Immunol. 1988 Mar 15;140(6):1753–1761. [PubMed]
  • Damle NK, Hansen JA, Good RA, Gupta S. Monoclonal antibody analysis of human T lymphocyte subpopulations exhibiting autologous mixed lymphocyte reaction. Proc Natl Acad Sci U S A. 1981 Aug;78(8):5096–5098. [PMC free article] [PubMed]
  • Lesslauer W, Koning F, Ottenhoff T, Giphart M, Goulmy E, van Rood JJ. T90/44 (9.3 antigen). A cell surface molecule with a function in human T cell activation. Eur J Immunol. 1986 Oct;16(10):1289–1296. [PubMed]
  • Williams AF, Barclay AN. The immunoglobulin superfamily--domains for cell surface recognition. Annu Rev Immunol. 1988;6:381–405. [PubMed]
  • Alzari PM, Lascombe MB, Poljak RJ. Three-dimensional structure of antibodies. Annu Rev Immunol. 1988;6:555–580. [PubMed]
  • Di Minno G, Thiagarajan P, Perussia B, Martinez J, Shapiro S, Trinchieri G, Murphy S. Exposure of platelet fibrinogen-binding sites by collagen, arachidonic acid, and ADP: inhibition by a monoclonal antibody to the glycoprotein IIb-IIIa complex. Blood. 1983 Jan;61(1):140–148. [PubMed]
  • Hautanen A, Gailit J, Mann DM, Ruoslahti E. Effects of modifications of the RGD sequence and its context on recognition by the fibronectin receptor. J Biol Chem. 1989 Jan 25;264(3):1437–1442. [PubMed]
  • Thiagarajan P, Kelly KL. Exposure of binding sites for vitronectin on platelets following stimulation. J Biol Chem. 1988 Feb 25;263(6):3035–3038. [PubMed]
  • Recny MA, Neidhardt EA, Sayre PH, Ciardelli TL, Reinherz EL. Structural and functional characterization of the CD2 immunoadhesion domain. Evidence for inclusion of CD2 in an alpha-beta protein folding class. J Biol Chem. 1990 May 25;265(15):8542–8549. [PubMed]
  • Clayton LK, Sieh M, Pious DA, Reinherz EL. Identification of human CD4 residues affecting class II MHC versus HIV-1 gp120 binding. Nature. 1989 Jun 15;339(6225):548–551. [PubMed]

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