Skip to main content
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
. 1992 Apr 1;89(7):2940–2944. doi: 10.1073/pnas.89.7.2940

Structure-function relationship among T-cell receptors specific for lysozyme peptides bound to Ab or Abm-12 molecules.

J A Kobori 1, L Hood 1, N Shastri 1
PMCID: PMC48779  PMID: 1313573

Abstract

The alpha beta T-cell receptor (TCR) recognizes antigenic peptides bound to major histocompatibility complex (MHC) molecules. In contrast to the antibody combining site, for which the antigen contact or complementarity-determining residues (CDRs) have been precisely defined, the location and function of the corresponding CDR regions of the alpha and beta TCR chains are not known. To develop a model system for systematic analysis of the CDRs of the alpha beta TCR, we isolated a panel of murine T-cell clones that recognize a lysozyme peptide containing residues 74-88 bound to either Ab or Abm-12 MHC class II molecules. Although these two MHC molecules differ by only three amino acid residues within the A beta chain, each of the T-cell clones was specific for peptide bound to the self-MHC molecule and did not recognize the same peptide bound to the other MHC molecule. The structural basis for this exquisite ligand specificity of the TCRs was analyzed by isolation and characterization of alpha and beta chain genes from five closely related T-cell clones. Comparison of predicted amino acid sequences mapped the ligand specificity differences to residues present within the alpha chain variable region segment and the alpha and beta chain variable-joining region junction regions. Thus with current models of TCR-ligand interactions, the results suggest that residues 26-30 of the alpha chain variable region may constitute one of the CDR regions of the TCR.

Full text

PDF
2940

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arden B., Klotz J. L., Siu G., Hood L. E. Diversity and structure of genes of the alpha family of mouse T-cell antigen receptor. 1985 Aug 29-Sep 4Nature. 316(6031):783–787. doi: 10.1038/316783a0. [DOI] [PubMed] [Google Scholar]
  2. Barth R. K., Kim B. S., Lan N. C., Hunkapiller T., Sobieck N., Winoto A., Gershenfeld H., Okada C., Hansburg D., Weissman I. L. The murine T-cell receptor uses a limited repertoire of expressed V beta gene segments. Nature. 1985 Aug 8;316(6028):517–523. doi: 10.1038/316517a0. [DOI] [PubMed] [Google Scholar]
  3. Bill J., Yagüe J., Appel V. B., White J., Horn G., Erlich H. A., Palmer E. Molecular genetic analysis of 178 I-Abm12-reactive T cells. J Exp Med. 1989 Jan 1;169(1):115–133. doi: 10.1084/jem.169.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blackman M., Kappler J., Marrack P. The role of the T cell receptor in positive and negative selection of developing T cells. Science. 1990 Jun 15;248(4961):1335–1341. doi: 10.1126/science.1972592. [DOI] [PubMed] [Google Scholar]
  5. Bluestone J. A., Cron R. Q., Cotterman M., Houlden B. A., Matis L. A. Structure and specificity of T cell receptor gamma/delta on major histocompatibility complex antigen-specific CD3+, CD4-, CD8- T lymphocytes. J Exp Med. 1988 Nov 1;168(5):1899–1916. doi: 10.1084/jem.168.5.1899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brown J. H., Jardetzky T., Saper M. A., Samraoui B., Bjorkman P. J., Wiley D. C. A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature. 1988 Apr 28;332(6167):845–850. doi: 10.1038/332845a0. [DOI] [PubMed] [Google Scholar]
  7. Chothia C., Boswell D. R., Lesk A. M. The outline structure of the T-cell alpha beta receptor. EMBO J. 1988 Dec 1;7(12):3745–3755. doi: 10.1002/j.1460-2075.1988.tb03258.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Davis M. M., Bjorkman P. J. T-cell antigen receptor genes and T-cell recognition. Nature. 1988 Aug 4;334(6181):395–402. doi: 10.1038/334395a0. [DOI] [PubMed] [Google Scholar]
  9. Engel I., Hedrick S. M. Site-directed mutations in the VDJ junctional region of a T cell receptor beta chain cause changes in antigenic peptide recognition. Cell. 1988 Aug 12;54(4):473–484. doi: 10.1016/0092-8674(88)90068-2. [DOI] [PubMed] [Google Scholar]
  10. Fink P. J., Matis L. A., McElligott D. L., Bookman M., Hedrick S. M. Correlations between T-cell specificity and the structure of the antigen receptor. Nature. 1986 May 15;321(6067):219–226. doi: 10.1038/321219a0. [DOI] [PubMed] [Google Scholar]
  11. Gascoigne N. R., Chien Y., Becker D. M., Kavaler J., Davis M. M. Genomic organization and sequence of T-cell receptor beta-chain constant- and joining-region genes. Nature. 1984 Aug 2;310(5976):387–391. doi: 10.1038/310387a0. [DOI] [PubMed] [Google Scholar]
  12. Glaichenhaus N., Davis C., Bornschlegel K., Allison J. P., Shastri N. A novel strategy for the generation of T cell lines lacking expression of endogenous alpha- and/or beta-chain T cell receptor genes. J Immunol. 1991 Apr 1;146(7):2095–2101. [PubMed] [Google Scholar]
  13. Goverman J., Minard K., Shastri N., Hunkapiller T., Hansburg D., Sercarz E., Hood L. Rearranged beta T cell receptor genes in a helper T cell clone specific for lysozyme: no correlation between V beta and MHC restriction. Cell. 1985 Apr;40(4):859–867. doi: 10.1016/0092-8674(85)90345-9. [DOI] [PubMed] [Google Scholar]
  14. Gubler U., Hoffman B. J. A simple and very efficient method for generating cDNA libraries. Gene. 1983 Nov;25(2-3):263–269. doi: 10.1016/0378-1119(83)90230-5. [DOI] [PubMed] [Google Scholar]
  15. Hedrick S. M., Engel I., McElligott D. L., Fink P. J., Hsu M. L., Hansburg D., Matis L. A. Selection of amino acid sequences in the beta chain of the T cell antigen receptor. Science. 1988 Mar 25;239(4847):1541–1544. doi: 10.1126/science.2832942. [DOI] [PubMed] [Google Scholar]
  16. Kappler J. W., Staerz U., White J., Marrack P. C. Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex. Nature. 1988 Mar 3;332(6159):35–40. doi: 10.1038/332035a0. [DOI] [PubMed] [Google Scholar]
  17. Kavaler J., Davis M. M., Chien Y. Localization of a T-cell receptor diversity-region element. Nature. 1984 Aug 2;310(5976):421–423. doi: 10.1038/310421a0. [DOI] [PubMed] [Google Scholar]
  18. Klotz J. L., Barth R. K., Kiser G. L., Hood L. E., Kronenberg M. Restriction fragment length polymorphisms of the mouse T-cell receptor gene families. Immunogenetics. 1989;29(3):191–201. doi: 10.1007/BF00373645. [DOI] [PubMed] [Google Scholar]
  19. Kobori J. A., Strauss E., Minard K., Hood L. Molecular analysis of the hotspot of recombination in the murine major histocompatibility complex. Science. 1986 Oct 10;234(4773):173–179. doi: 10.1126/science.3018929. [DOI] [PubMed] [Google Scholar]
  20. Kronenberg M., Goverman J., Haars R., Malissen M., Kraig E., Phillips L., Delovitch T., Suciu-Foca N., Hood L. Rearrangement and transcription of the beta-chain genes of the T-cell antigen receptor in different types of murine lymphocytes. Nature. 1985 Feb 21;313(6004):647–653. doi: 10.1038/313647a0. [DOI] [PubMed] [Google Scholar]
  21. Kronenberg M., Siu G., Hood L. E., Shastri N. The molecular genetics of the T-cell antigen receptor and T-cell antigen recognition. Annu Rev Immunol. 1986;4:529–591. doi: 10.1146/annurev.iy.04.040186.002525. [DOI] [PubMed] [Google Scholar]
  22. Loh E. Y., Lanier L. L., Turck C. W., Littman D. R., Davis M. M., Chien Y. H., Weiss A. Identification and sequence of a fourth human T cell antigen receptor chain. Nature. 1987 Dec 10;330(6148):569–572. doi: 10.1038/330569a0. [DOI] [PubMed] [Google Scholar]
  23. MacDonald H. R., Schneider R., Lees R. K., Howe R. C., Acha-Orbea H., Festenstein H., Zinkernagel R. M., Hengartner H. T-cell receptor V beta use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature. 1988 Mar 3;332(6159):40–45. doi: 10.1038/332040a0. [DOI] [PubMed] [Google Scholar]
  24. Madden D. R., Gorga J. C., Strominger J. L., Wiley D. C. The structure of HLA-B27 reveals nonamer self-peptides bound in an extended conformation. Nature. 1991 Sep 26;353(6342):321–325. doi: 10.1038/353321a0. [DOI] [PubMed] [Google Scholar]
  25. Malissen M., Minard K., Mjolsness S., Kronenberg M., Goverman J., Hunkapiller T., Prystowsky M. B., Yoshikai Y., Fitch F., Mak T. W. Mouse T cell antigen receptor: structure and organization of constant and joining gene segments encoding the beta polypeptide. Cell. 1984 Jul;37(3):1101–1110. doi: 10.1016/0092-8674(84)90444-6. [DOI] [PubMed] [Google Scholar]
  26. Malissen M., Trucy J., Letourneur F., Rebaï N., Dunn D. E., Fitch F. W., Hood L., Malissen B. A T cell clone expresses two T cell receptor alpha genes but uses one alpha beta heterodimer for allorecognition and self MHC-restricted antigen recognition. Cell. 1988 Oct 7;55(1):49–59. doi: 10.1016/0092-8674(88)90008-6. [DOI] [PubMed] [Google Scholar]
  27. Matis L. A. The molecular basis of T-cell specificity. Annu Rev Immunol. 1990;8:65–82. doi: 10.1146/annurev.iy.08.040190.000433. [DOI] [PubMed] [Google Scholar]
  28. McIntyre K. R., Seidman J. G. Nucleotide sequence of mutant I-A beta bm12 gene is evidence for genetic exchange between mouse immune response genes. Nature. 1984 Apr 5;308(5959):551–553. doi: 10.1038/308551a0. [DOI] [PubMed] [Google Scholar]
  29. Ronchese F., Brown M. A., Germain R. N. Structure-function analysis of the Abm12 beta mutation using site-directed mutagenesis and DNA-mediated gene transfer. J Immunol. 1987 Jul 15;139(2):629–638. [PubMed] [Google Scholar]
  30. Rudensky AYu, Preston-Hurlburt P., Hong S. C., Barlow A., Janeway C. A., Jr Sequence analysis of peptides bound to MHC class II molecules. Nature. 1991 Oct 17;353(6345):622–627. doi: 10.1038/353622a0. [DOI] [PubMed] [Google Scholar]
  31. Schwartz R. H. T-lymphocyte recognition of antigen in association with gene products of the major histocompatibility complex. Annu Rev Immunol. 1985;3:237–261. doi: 10.1146/annurev.iy.03.040185.001321. [DOI] [PubMed] [Google Scholar]
  32. Shastri N., Gammon G., Horvath S., Miller A., Sercarz E. E. The choice between two distinct T cell determinants within a 23-amino acid region of lysozyme depends on their structural context. J Immunol. 1986 Aug 1;137(3):911–915. [PubMed] [Google Scholar]
  33. Shastri N., Gammon G., Miller A., Sercarz E. E. Ia molecule-associated selectivity in T cell recognition of a 23-amino-acid peptide of lysozyme. J Exp Med. 1986 Sep 1;164(3):882–896. doi: 10.1084/jem.164.3.882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Shastri N., Oki A., Miller A., Sercarz E. E. Distinct recognition phenotypes exist for T cell clones specific for small peptide regions of proteins. Implications for the mechanisms underlying major histocompatibility complex-restricted antigen recognition and clonal deletion models of immune response gene defects. J Exp Med. 1985 Jul 1;162(1):332–345. doi: 10.1084/jem.162.1.332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sitkovsky M. V., Paul W. E. Immunology. Global or directed exocytosis? Nature. 1988 Mar 24;332(6162):306–307. doi: 10.1038/332306a0. [DOI] [PubMed] [Google Scholar]
  36. Siu G., Kronenberg M., Strauss E., Haars R., Mak T. W., Hood L. The structure, rearrangement and expression of D beta gene segments of the murine T-cell antigen receptor. 1984 Sep 27-Oct 3Nature. 311(5984):344–350. doi: 10.1038/311344a0. [DOI] [PubMed] [Google Scholar]
  37. Strauss E. C., Kobori J. A., Siu G., Hood L. E. Specific-primer-directed DNA sequencing. Anal Biochem. 1986 Apr;154(1):353–360. doi: 10.1016/0003-2697(86)90536-1. [DOI] [PubMed] [Google Scholar]
  38. Urban J. L., Kumar V., Kono D. H., Gomez C., Horvath S. J., Clayton J., Ando D. G., Sercarz E. E., Hood L. Restricted use of T cell receptor V genes in murine autoimmune encephalomyelitis raises possibilities for antibody therapy. Cell. 1988 Aug 12;54(4):577–592. doi: 10.1016/0092-8674(88)90079-7. [DOI] [PubMed] [Google Scholar]
  39. White J., Herman A., Pullen A. M., Kubo R., Kappler J. W., Marrack P. The V beta-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice. Cell. 1989 Jan 13;56(1):27–35. doi: 10.1016/0092-8674(89)90980-x. [DOI] [PubMed] [Google Scholar]
  40. Winoto A., Mjolsness S., Hood L. Genomic organization of the genes encoding mouse T-cell receptor alpha-chain. 1985 Aug 29-Sep 4Nature. 316(6031):832–836. doi: 10.1038/316832a0. [DOI] [PubMed] [Google Scholar]
  41. Winoto A., Urban J. L., Lan N. C., Goverman J., Hood L., Hansburg D. Predominant use of a V alpha gene segment in mouse T-cell receptors for cytochrome c. Nature. 1986 Dec 18;324(6098):679–682. doi: 10.1038/324679a0. [DOI] [PubMed] [Google Scholar]
  42. von Boehmer H., Kisielow P. Self-nonself discrimination by T cells. Science. 1990 Jun 15;248(4961):1369–1373. doi: 10.1126/science.1972594. [DOI] [PubMed] [Google Scholar]
  43. von Heijne G. Patterns of amino acids near signal-sequence cleavage sites. Eur J Biochem. 1983 Jun 1;133(1):17–21. doi: 10.1111/j.1432-1033.1983.tb07424.x. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES