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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Sep 1;90(17):8259–8263. doi: 10.1073/pnas.90.17.8259

Delineation of an extended surface contact area on human CD4 involved in class II major histocompatibility complex binding.

U Moebius 1, P Pallai 1, S C Harrison 1, E L Reinherz 1
PMCID: PMC47328  PMID: 8367491

Abstract

We describe a detailed mapping of the class II major histocompatibility complex (MHC) binding site using site-directed mutagenesis in conjunction with high-resolution CD4 structural data. Residues on all lateral surfaces of domain 1 and the neighboring portions of domain 2 participate in contacting class II MHC. Thus, in addition to the C'C" ridge that forms the human immunodeficiency virus type 1 gp120 binding site, apparent MHC contacts extend over the BED face of domain 1 and across the interdomain groove onto the FG loop of domain 2. Several models of the CD4/class II MHC interaction accounting for the extent of the CD4 surface involved are discussed, including the possibility that CD4 may contact more than one class II MHC molecule using different surfaces.

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Selected References

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  1. Alcover A., Weiss M. J., Daley J. F., Reinherz E. L. The T11 glycoprotein is functionally linked to a calcium channel in precursor and mature T-lineage cells. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2614–2618. doi: 10.1073/pnas.83.8.2614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Biddison W. E., Rao P. E., Talle M. A., Goldstein G., Shaw S. Possible involvement of the OKT4 molecule in T cell recognition of class II HLA antigens. Evidence from studies of cytotoxic T lymphocytes specific for SB antigens. J Exp Med. 1982 Oct 1;156(4):1065–1076. doi: 10.1084/jem.156.4.1065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bowman M. R., MacFerrin K. D., Schreiber S. L., Burakoff S. J. Identification and structural analysis of residues in the V1 region of CD4 involved in interaction with human immunodeficiency virus envelope glycoprotein gp120 and class II major histocompatibility complex molecules. Proc Natl Acad Sci U S A. 1990 Nov;87(22):9052–9056. doi: 10.1073/pnas.87.22.9052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brown J. H., Jardetzky T. S., Gorga J. C., Stern L. J., Urban R. G., Strominger J. L., Wiley D. C. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature. 1993 Jul 1;364(6432):33–39. doi: 10.1038/364033a0. [DOI] [PubMed] [Google Scholar]
  5. Clayton L. K., Sieh M., Pious D. A., Reinherz E. L. Identification of human CD4 residues affecting class II MHC versus HIV-1 gp120 binding. Nature. 1989 Jun 15;339(6225):548–551. doi: 10.1038/339548a0. [DOI] [PubMed] [Google Scholar]
  6. Dalgleish A. G., Beverley P. C., Clapham P. R., Crawford D. H., Greaves M. F., Weiss R. A. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature. 1984 Dec 20;312(5996):763–767. doi: 10.1038/312763a0. [DOI] [PubMed] [Google Scholar]
  7. Davis S. J., Schockmel G. A., Somoza C., Buck D. W., Healey D. G., Rieber E. P., Reiter C., Williams A. F. Antibody and HIV-1 gp120 recognition of CD4 undermines the concept of mimicry between antibodies and receptors. Nature. 1992 Jul 2;358(6381):76–79. doi: 10.1038/358076a0. [DOI] [PubMed] [Google Scholar]
  8. Doyle C., Strominger J. L. Interaction between CD4 and class II MHC molecules mediates cell adhesion. Nature. 1987 Nov 19;330(6145):256–259. doi: 10.1038/330256a0. [DOI] [PubMed] [Google Scholar]
  9. Engleman E. G., Benike C. J., Grumet F. C., Evans R. L. Activation of human T lymphocyte subsets: helper and suppressor/cytotoxic T cells recognize and respond to distinct histocompatibility antigens. J Immunol. 1981 Nov;127(5):2124–2129. [PubMed] [Google Scholar]
  10. Fleury S., Lamarre D., Meloche S., Ryu S. E., Cantin C., Hendrickson W. A., Sekaly R. P. Mutational analysis of the interaction between CD4 and class II MHC: class II antigens contact CD4 on a surface opposite the gp120-binding site. Cell. 1991 Sep 6;66(5):1037–1049. doi: 10.1016/0092-8674(91)90447-7. [DOI] [PubMed] [Google Scholar]
  11. Harrison S. C., Wang J., Yan Y., Garrett T., Liu J., Moebius U., Reinherz E. Structure and interactions of CD4. Cold Spring Harb Symp Quant Biol. 1992;57:541–548. doi: 10.1101/sqb.1992.057.01.059. [DOI] [PubMed] [Google Scholar]
  12. Klatzmann D., Champagne E., Chamaret S., Gruest J., Guetard D., Hercend T., Gluckman J. C., Montagnier L. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature. 1984 Dec 20;312(5996):767–768. doi: 10.1038/312767a0. [DOI] [PubMed] [Google Scholar]
  13. Krensky A. M., Reiss C. S., Mier J. W., Strominger J. L., Burakoff S. J. Long-term human cytolytic T-cell lines allospecific for HLA-DR6 antigen are OKT4+. Proc Natl Acad Sci U S A. 1982 Apr;79(7):2365–2369. doi: 10.1073/pnas.79.7.2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kupfer A., Singer S. J., Janeway C. A., Jr, Swain S. L. Coclustering of CD4 (L3T4) molecule with the T-cell receptor is induced by specific direct interaction of helper T cells and antigen-presenting cells. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5888–5892. doi: 10.1073/pnas.84.16.5888. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. König R., Huang L. Y., Germain R. N. MHC class II interaction with CD4 mediated by a region analogous to the MHC class I binding site for CD8. Nature. 1992 Apr 30;356(6372):796–798. doi: 10.1038/356796a0. [DOI] [PubMed] [Google Scholar]
  16. Lamarre D., Ashkenazi A., Fleury S., Smith D. H., Sekaly R. P., Capon D. J. The MHC-binding and gp120-binding functions of CD4 are separable. Science. 1989 Aug 18;245(4919):743–746. doi: 10.1126/science.2549633. [DOI] [PubMed] [Google Scholar]
  17. Maddon P. J., Dalgleish A. G., McDougal J. S., Clapham P. R., Weiss R. A., Axel R. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell. 1986 Nov 7;47(3):333–348. doi: 10.1016/0092-8674(86)90590-8. [DOI] [PubMed] [Google Scholar]
  18. Maddon P. J., Littman D. R., Godfrey M., Maddon D. E., Chess L., Axel R. The isolation and nucleotide sequence of a cDNA encoding the T cell surface protein T4: a new member of the immunoglobulin gene family. Cell. 1985 Aug;42(1):93–104. doi: 10.1016/s0092-8674(85)80105-7. [DOI] [PubMed] [Google Scholar]
  19. McDougal J. S., Mawle A., Cort S. P., Nicholson J. K., Cross G. D., Scheppler-Campbell J. A., Hicks D., Sligh J. Cellular tropism of the human retrovirus HTLV-III/LAV. I. Role of T cell activation and expression of the T4 antigen. J Immunol. 1985 Nov;135(5):3151–3162. [PubMed] [Google Scholar]
  20. Meuer S. C., Hussey R. E., Hodgdon J. C., Hercend T., Schlossman S. F., Reinherz E. L. Surface structures involved in target recognition by human cytotoxic T lymphocytes. Science. 1982 Oct 29;218(4571):471–473. doi: 10.1126/science.6981845. [DOI] [PubMed] [Google Scholar]
  21. Meuer S. C., Schlossman S. F., Reinherz E. L. Clonal analysis of human cytotoxic T lymphocytes: T4+ and T8+ effector T cells recognize products of different major histocompatibility complex regions. Proc Natl Acad Sci U S A. 1982 Jul;79(14):4395–4399. doi: 10.1073/pnas.79.14.4395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Moebius U., Clayton L. K., Abraham S., Diener A., Yunis J. J., Harrison S. C., Reinherz E. L. Human immunodeficiency virus gp120 binding C'C" ridge of CD4 domain 1 is also involved in interaction with class II major histocompatibility complex molecules. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12008–12012. doi: 10.1073/pnas.89.24.12008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Moebius U., Clayton L. K., Abraham S., Harrison S. C., Reinherz E. L. The human immunodeficiency virus gp120 binding site on CD4: delineation by quantitative equilibrium and kinetic binding studies of mutants in conjunction with a high-resolution CD4 atomic structure. J Exp Med. 1992 Aug 1;176(2):507–517. doi: 10.1084/jem.176.2.507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Peterson A., Seed B. Genetic analysis of monoclonal antibody and HIV binding sites on the human lymphocyte antigen CD4. Cell. 1988 Jul 1;54(1):65–72. doi: 10.1016/0092-8674(88)90180-8. [DOI] [PubMed] [Google Scholar]
  25. Peterson A., Seed B. Monoclonal antibody and ligand binding sites of the T cell erythrocyte receptor (CD2). 1987 Oct 29-Nov 4Nature. 329(6142):842–846. doi: 10.1038/329842a0. [DOI] [PubMed] [Google Scholar]
  26. Reinherz E. L., Kung P. C., Goldstein G., Schlossman S. F. Separation of functional subsets of human T cells by a monoclonal antibody. Proc Natl Acad Sci U S A. 1979 Aug;76(8):4061–4065. doi: 10.1073/pnas.76.8.4061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Reinherz E. L., Morimoto C., Penta A. C., Schlossman S. F. Regulation of B cell immunoglobulin secretion by functional subsets of T lymphocytes in man. Eur J Immunol. 1980 Jul;10(7):570–572. doi: 10.1002/eji.1830100715. [DOI] [PubMed] [Google Scholar]
  28. Rudd C. E., Trevillyan J. M., Dasgupta J. D., Wong L. L., Schlossman S. F. The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5190–5194. doi: 10.1073/pnas.85.14.5190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ryu S. E., Kwong P. D., Truneh A., Porter T. G., Arthos J., Rosenberg M., Dai X. P., Xuong N. H., Axel R., Sweet R. W. Crystal structure of an HIV-binding recombinant fragment of human CD4. Nature. 1990 Nov 29;348(6300):419–426. doi: 10.1038/348419a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Saizawa K., Rojo J., Janeway C. A., Jr Evidence for a physical association of CD4 and the CD3:alpha:beta T-cell receptor. Nature. 1987 Jul 16;328(6127):260–263. doi: 10.1038/328260a0. [DOI] [PubMed] [Google Scholar]
  31. Sanders S. K., Fox R. O., Kavathas P. Mutations in CD8 that affect interactions with HLA class I and monoclonal anti-CD8 antibodies. J Exp Med. 1991 Aug 1;174(2):371–379. doi: 10.1084/jem.174.2.371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sattentau Q. J., Arthos J., Deen K., Hanna N., Healey D., Beverley P. C., Sweet R., Truneh A. Structural analysis of the human immunodeficiency virus-binding domain of CD4. Epitope mapping with site-directed mutants and anti-idiotypes. J Exp Med. 1989 Oct 1;170(4):1319–1334. doi: 10.1084/jem.170.4.1319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Veillette A., Bookman M. A., Horak E. M., Bolen J. B. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell. 1988 Oct 21;55(2):301–308. doi: 10.1016/0092-8674(88)90053-0. [DOI] [PubMed] [Google Scholar]
  34. Wang J. H., Yan Y. W., Garrett T. P., Liu J. H., Rodgers D. W., Garlick R. L., Tarr G. E., Husain Y., Reinherz E. L., Harrison S. C. Atomic structure of a fragment of human CD4 containing two immunoglobulin-like domains. Nature. 1990 Nov 29;348(6300):411–418. doi: 10.1038/348411a0. [DOI] [PubMed] [Google Scholar]

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