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PMID: 7535334 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Mutational analysis and an alternatively spliced product of B7 defines its CD28/CTLA4-binding site on immunoglobulin C-like domain.

The Journal of experimental medicine ·Vol. 181 ·No. 4 ·1995-04-01 ·Pages 1345-55

Guo Y, Wu Y, Zhao M, Kong XP, Liu Y

Abstract

Costimulatory molecules B7 and B7-2 interact with T cell surface receptors CD28/CTLA4 and deliver a costimulatory signal essential for T cell growth. However, the structure basis of this interaction is not known. B7 and B7-2 are members of immunoglobulin (Ig) superfamily and their extracellular portion consists of an IgV- and IgC-like domain. Here we report that a naturally occurring, alternatively spliced form of B7 reveals that exon 3-encoded IgC domain is essential for CD28/CTLA4 binding. Mutational analysis of B7 demonstrates a critical role of several amino acids around loops between strands B and C and D and E, for binding CTLA4/CD28. These amino acids are clustered to form a single binding site centered at 201Y. A comparison of the effects of mutations on the binding of CD28 and CTLA4 reveals that CD28 and CTLA4 binds to the same site on B7. These results have important implications on the role of CTLA4 and CD28 in T cell costimulation. The structure of the CD28/CTLA4-binding site also provides valuable information for immune intervention targeted at the B7/B7-2-CD28/CTLA4 interactions.

MeSH Terms
Abatacept Amino Acid Sequence Animals Antigens, CD Antigens, Differentiation/metabolism B7-1 Antigen/chemistry,genetics,metabolism B7-2 Antigen Base Sequence Binding Sites CD28 Antigens/metabolism CHO Cells CTLA-4 Antigen Cell Line, Transformed Chlorocebus aethiops Cricetinae DNA Mutational Analysis Immunoconjugates Immunoglobulin Constant Regions/chemistry Lymphocyte Activation Membrane Glycoproteins/metabolism Mice Mice, Inbred CBA Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Polymerase Chain Reaction Protein Structure, Tertiary RNA Splicing Structure-Activity Relationship
Chemicals
Antigens, CD Antigens, Differentiation B7-1 Antigen B7-2 Antigen CD28 Antigens CTLA-4 Antigen Cd86 protein, mouse Ctla4 protein, mouse Immunoconjugates Immunoglobulin Constant Regions Membrane Glycoproteins Abatacept
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Guo Y
Michael Heidelberger Division of Immunology, Department of Pathology, New York University Medical Center, New York 10016, USA.
Wu Y
Zhao M
Kong X P
Liu Y
References (45)
45 references, click to expand
  1. Structure, expression, and T cell costimulatory activity of the murine homologue of the human B lymphocyte activation antigen B7.
    J Exp Med. 1991 Sep 1;174(3):625-31 PMID: 1714935
  2. In vitro induction of T cell anergy by blocking B7 and early T cell costimulatory molecule ETC-1/B7-2.
    Immunity. 1994 May;1(2):147-54 PMID: 7534198
  3. Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals.
    J Exp Med. 1992 Feb 1;175(2):331-40 PMID: 1346269
  4. Heat-stable antigen is a costimulatory molecule for CD4 T cell growth.
    J Exp Med. 1992 Feb 1;175(2):437-45 PMID: 1346270
  5. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones.
    Nature. 1992 Apr 16;356(6370):607-9 PMID: 1313950
  6. Expression and function of the murine B7 antigen, the major costimulatory molecule expressed by peritoneal exudate cells.
    Proc Natl Acad Sci U S A. 1992 May 1;89(9):4210-4 PMID: 1373896
  7. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg.
    Science. 1992 Aug 7;257(5071):789-92 PMID: 1323143
  8. Costimulation of T-cell growth.
    Curr Opin Immunol. 1992 Jun;4(3):265-70 PMID: 1418704
  9. Co-stimulation of murine CD4 T cell growth: cooperation between B7 and heat-stable antigen.
    Eur J Immunol. 1992 Nov;22(11):2855-9 PMID: 1385153
  10. T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo.
    Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):11102-5 PMID: 1332070
  11. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes.
    J Exp Med. 1992 Dec 1;176(6):1595-604 PMID: 1334116
  12. A theory of self-nonself discrimination.
    Science. 1970 Sep 11;169(3950):1042-9 PMID: 4194660
  13. A new analysis of allogeneic interactions.
    Aust J Exp Biol Med Sci. 1975 Feb;53(1):27-42 PMID: 238498
  14. Preliminary refinement and structural analysis of the Fab fragment from human immunoglobulin new at 2.0 A resolution.
    J Biol Chem. 1978 Jan 25;253(2):585-97 PMID: 618887
  15. Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors.
    J Exp Med. 1979 Sep 19;150(3):580-96 PMID: 90108
  16. IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt 2 antigen block T cell-mediated cytolysis in the absence of complement.
    J Immunol. 1980 Dec;125(6):2665-72 PMID: 6159417
  17. Use of a monoclonal antibody specifically non-reactive with T cells to delineate lymphocyte subpopulations.
    Immunology. 1981 Mar;42(3):371-8 PMID: 7009413
  18. A monoclonal antibody discriminating between subsets of T and B cells.
    J Immunol. 1981 Dec;127(6):2496-501 PMID: 6975326
  19. Mapping of antigenic and functional epitopes on the alpha- and beta-subunits of two related mouse glycoproteins involved in cell interactions, LFA-1 and Mac-1.
    J Exp Med. 1983 Aug 1;158(2):586-602 PMID: 6193226
  20. Human T cell activation. II. A new activation pathway used by a major T cell population via a disulfide-bonded dimer of a 44 kilodalton polypeptide (9.3 antigen).
    J Exp Med. 1985 Jun 1;161(6):1513-24 PMID: 3159820
  21. Involvement of T44 molecules in an antigen-independent pathway of T cell activation. Analysis of the correlations to the T cell antigen-receptor complex.
    J Exp Med. 1985 Sep 1;162(3):823-38 PMID: 3875683
  22. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo.
    J Exp Med. 1987 Feb 1;165(2):302-19 PMID: 3029267
  23. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy.
    Annu Rev Immunol. 1989;7:445-80 PMID: 2653373
  24. B7, a new member of the Ig superfamily with unique expression on activated and neoplastic B cells.
    J Immunol. 1989 Oct 15;143(8):2714-22 PMID: 2794510
  25. The murine homologue of the T lymphocyte antigen CD28. Molecular cloning and cell surface expression.
    J Immunol. 1990 Apr 15;144(8):3201-10 PMID: 2157764
  26. 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):5031-5 PMID: 2164219
  27. Interferon gamma plays a critical role in induced cell death of effector T cell: a possible third mechanism of self-tolerance.
    J Exp Med. 1990 Dec 1;172(6):1735-9 PMID: 2147950
  28. 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):721-30 PMID: 1847722
  29. Vascular cell adhesion molecule 1 induces T-cell antigen receptor-dependent activation of CD4+T lymphocytes.
    Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6403-7 PMID: 1713678
  30. CTLA-4 is a second receptor for the B cell activation antigen B7.
    J Exp Med. 1991 Sep 1;174(3):561-9 PMID: 1714933
  31. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4.
    Cell. 1992 Dec 24;71(7):1093-102 PMID: 1335364
  32. Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1.
    J Exp Med. 1993 Jan 1;177(1):165-73 PMID: 7678111
  33. Tumor rejection after direct costimulation of CD8+ T cells by B7-transfected melanoma cells.
    Science. 1993 Jan 15;259(5093):368-70 PMID: 7678351
  34. Linkage of superantigen-like stimulation of syngeneic T cells in a mouse model of follicular center B cell lymphoma to transcription of endogenous mammary tumor virus.
    EMBO J. 1993 Jun;12(6):2313-20 PMID: 8389694
  35. CD3-mediated apoptosis of human medullary thymocytes and activated peripheral T cells: respective roles of interleukin-1, interleukin-2, interferon-gamma and accessory cells.
    Eur J Immunol. 1993 Jul;23(7):1623-9 PMID: 8325338
  36. Molecules involved in T-cell costimulation.
    Curr Opin Immunol. 1993 Jun;5(3):361-7 PMID: 7688514
  37. A major costimulatory molecule on antigen-presenting cells, CTLA4 ligand A, is distinct from B7.
    J Exp Med. 1993 Nov 1;178(5):1789-93 PMID: 8228824
  38. Identification of an alternative CTLA-4 ligand costimulatory for T cell activation.
    Science. 1993 Nov 5;262(5135):905-7 PMID: 7694361
  39. Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice.
    Science. 1993 Nov 5;262(5135):907-9 PMID: 7694362
  40. Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation.
    Science. 1993 Nov 5;262(5135):909-11 PMID: 7694363
  41. Murine B7-2, an alternative CTLA4 counter-receptor that costimulates T cell proliferation and interleukin 2 production.
    J Exp Med. 1993 Dec 1;178(6):2185-92 PMID: 7504059
  42. Costimulation of T lymphocytes with integrin ligands intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 induces functional expression of CTLA-4, a second receptor for B7.
    J Immunol. 1994 Mar 15;152(6):2686-97 PMID: 7511623
  43. T cell costimulation by B7/BB1 induces CD8 T cell-dependent tumor rejection: an important role of B7/BB1 in the induction, recruitment, and effector function of antitumor T cells.
    J Exp Med. 1994 Apr 1;179(4):1205-14 PMID: 7511683
  44. Identification of an alternatively spliced form of the murine homologue of B7.
    Biochem Biophys Res Commun. 1994 Apr 15;200(1):443-9 PMID: 7513163
  45. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells.
    J Immunol. 1991 Oct 15;147(8):2461-6 PMID: 1717561
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.181.4.1345
Published
1995-04-01
Pages
1345-55
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2191977
Subset
IM
Grants
NIAID NIH HHS · AI-32981 · United States
NCI NIH HHS · CA-16087 · United States
NCI NIH HHS · CA-58033 · United States
External Links
PubMed source DOI: 10.1084/jem.181.4.1345 PMC Full Text View journal details
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