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J Exp Med. 1990 July 1; 172(1): 27–33.
PMCID: PMC2188142

The presumptive CDR3 regions of both T cell receptor alpha and beta chains determine T cell specificity for myoglobin peptides

Abstract

The T cell receptor alpha/beta (TCR-alpha/beta) is encoded by variable (V), diversity (D), joining (J), and constant (C) segments assembled by recombination during thymocyte maturation to produce a heterodimer that imparts antigenic specificity to the T cell. Unlike immunoglobulins (Igs), which bind free antigen, the ligands of TCR-alpha/beta are cell surface complexes of intracellularly degraded antigens (i.e., peptides) bound to and presented by polymorphic products of the major histocompatibility complex (MHC). Therefore, antigen recognition by T cells is defined as MHC restricted. A model has been formulated based upon the similarity between TCR-alpha/beta V region and Ig Fab amino acid sequences, and the crystal structure of the MHC class I and Ig molecules. This model predicts that the complementarity determining regions (CDR) 1 and 2, composed of TCR V alpha and V beta segments, primarily contact residues of the MHC alpha helices, whereas V/J alpha and V/D/J beta junctional regions (the CDR3 equivalent) contact the peptide in the MHC binding groove. Because polymorphism in MHC proteins is limited relative to the enormous diversity of antigenic peptides, the TCR may have evolved to position the highly diverse junctional residues (CDR3), where they have maximal contact with antigen bound in the MHC peptide groove. Here, we demonstrate a definitive association between CDR3 sequences in both TCR alpha and beta chains, and differences in recognition of antigen fine specificity using a panel of I-Ed-restricted, myoglobin-reactive T cell clones. Acquisition of these data relied in part upon a modification of the polymerase chain reaction that uses a degenerate, consensus primer to amplify TCR alpha chains without foreknowledge of the V alpha segments they utilize.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Allison JP, Lanier LL. Structure, function, and serology of the T-cell antigen receptor complex. Annu Rev Immunol. 1987;5:503–540. [PubMed]
  • Berzofsky JA, Brett SJ, Streicher HZ, Takahashi H. Antigen processing for presentation to T lymphocytes: function, mechanisms, and implications for the T-cell repertoire. Immunol Rev. 1988 Dec;106:5–31. [PubMed]
  • Davis MM, Bjorkman PJ. T-cell antigen receptor genes and T-cell recognition. Nature. 1988 Aug 4;334(6181):395–402. [PubMed]
  • Chothia C, Boswell DR, Lesk AM. The outline structure of the T-cell alpha beta receptor. EMBO J. 1988 Dec 1;7(12):3745–3755. [PubMed]
  • Infante AJ, Atassi MZ, Fathman CG. T cell clones reactive with sperm whale myoglobin. Isolation of clones with specificity for individual determinants on myoglobin. J Exp Med. 1981 Nov 1;154(5):1342–1356. [PMC free article] [PubMed]
  • Berkower I, Matis LA, Buckenmeyer GK, Gurd FR, Longo DL, Berzofsky JA. Identification of distinct predominant epitopes recognized by myoglobin-specific T cells under the control of different Ir genes and characterization of representative T cell clones. J Immunol. 1984 Mar;132(3):1370–1378. [PubMed]
  • Cease KB, Berkower I, York-Jolley J, Berzofsky JA. T cell clones specific for an amphipathic alpha-helical region of sperm whale myoglobin show differing fine specificities for synthetic peptides. A multiview/single structure interpretation of immunodominance. J Exp Med. 1986 Nov 1;164(5):1779–1784. [PMC free article] [PubMed]
  • Brown JH, Jardetzky T, Saper MA, Samraoui B, Bjorkman PJ, Wiley DC. A hypothetical model of the foreign antigen binding site of class II histocompatibility molecules. Nature. 1988 Apr 28;332(6167):845–850. [PubMed]
  • Garrett TP, Saper MA, Bjorkman PJ, Strominger JL, Wiley DC. Specificity pockets for the side chains of peptide antigens in HLA-Aw68. Nature. 1989 Dec 7;342(6250):692–696. [PubMed]
  • Fink PJ, Matis LA, McElligott DL, Bookman M, Hedrick SM. Correlations between T-cell specificity and the structure of the antigen receptor. Nature. 1986 May 15;321(6067):219–226. [PubMed]
  • Spinella DG, Hansen TH, Walsh WD, Behlke MA, Tillinghast JP, Chou HS, Whiteley PJ, Kapp JA, Pierce CW, Shevach EM, et al. Receptor diversity of insulin-specific T cell lines from C57BL (H-2b) mice. J Immunol. 1987 Jun 1;138(11):3991–3995. [PubMed]
  • Lai MZ, Huang SY, Briner TJ, Guillet JG, Smith JA, Gefter ML. T cell receptor gene usage in the response to lambda repressor cI protein. An apparent bias in the usage of a V alpha gene element. J Exp Med. 1988 Sep 1;168(3):1081–1097. [PMC free article] [PubMed]
  • Acha-Orbea H, Mitchell DJ, Timmermann L, Wraith DC, Tausch GS, Waldor MK, Zamvil SS, McDevitt HO, Steinman L. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell. 1988 Jul 15;54(2):263–273. [PubMed]
  • Kimoto M, Fathman CG. Antigen-reactive T cell clones. I. Transcomplementing hybrid I-A-region gene products function effectively in antigen presentation. J Exp Med. 1980 Oct 1;152(4):759–770. [PMC free article] [PubMed]
  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. [PubMed]
  • Gubler U, Hoffman BJ. A simple and very efficient method for generating cDNA libraries. Gene. 1983 Nov;25(2-3):263–269. [PubMed]
  • Malissen M, Minard K, Mjolsness S, Kronenberg M, Goverman J, Hunkapiller T, Prystowsky MB, Yoshikai Y, Fitch F, Mak TW, et al. 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. [PubMed]
  • Barth RK, Kim BS, Lan NC, Hunkapiller T, Sobieck N, Winoto A, Gershenfeld H, Okada C, Hansburg D, Weissman IL, et al. The murine T-cell receptor uses a limited repertoire of expressed V beta gene segments. Nature. 1985 Aug 8;316(6028):517–523. [PubMed]
  • Mullis KB, Faloona FA. Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Methods Enzymol. 1987;155:335–350. [PubMed]
  • Scharf SJ, Horn GT, Erlich HA. Direct cloning and sequence analysis of enzymatically amplified genomic sequences. Science. 1986 Sep 5;233(4768):1076–1078. [PubMed]
  • Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. [PubMed]
  • Feinberg AP, Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PubMed]
  • Becker DM, Pattern P, Chien Y, Yokota T, Eshhar Z, Giedlin M, Gascoigne NR, Goodnow C, Wolf R, Arai K, et al. Variability and repertoire size of T-cell receptor V alpha gene segments. Nature. 1985 Oct 3;317(6036):430–434. [PubMed]
  • McElligott DL, Sorger SB, Matis LA, Hedrick SM. Two distinct mechanisms account for the immune response (Ir) gene control of the T cell response to pigeon cytochrome c. J Immunol. 1988 Jun 15;140(12):4123–4131. [PubMed]
  • Yague J, Blackman M, Born W, Marrack P, Kappler J, Palmer E. The structure of V alpha and J alpha segments in the mouse. Nucleic Acids Res. 1988 Dec 9;16(23):11355–11364. [PMC free article] [PubMed]
  • Crews S, Griffin J, Huang H, Calame K, Hood L. A single VH gene segment encodes the immune response to phosphorylcholine: somatic mutation is correlated with the class of the antibody. Cell. 1981 Jul;25(1):59–66. [PubMed]
  • Morel PA, Livingstone AM, Fathman CG. Correlation of T cell receptor V beta gene family with MHC restriction. J Exp Med. 1987 Aug 1;166(2):583–588. [PMC free article] [PubMed]
  • Haskins K, Hannum C, White J, Roehm N, Kubo R, Kappler J, Marrack P. The antigen-specific, major histocompatibility complex-restricted receptor on T cells. VI. An antibody to a receptor allotype. J Exp Med. 1984 Aug 1;160(2):452–471. [PMC free article] [PubMed]
  • Staerz UD, Rammensee HG, Benedetto JD, Bevan MJ. Characterization of a murine monoclonal antibody specific for an allotypic determinant on T cell antigen receptor. J Immunol. 1985 Jun;134(6):3994–4000. [PubMed]
  • Liao NS, Maltzman J, Raulet DH. Positive selection determines T cell receptor V beta 14 gene usage by CD8+ T cells. J Exp Med. 1989 Jul 1;170(1):135–143. [PMC free article] [PubMed]
  • Wilson RK, Lai E, Concannon P, Barth RK, Hood LE. Structure, organization and polymorphism of murine and human T-cell receptor alpha and beta chain gene families. Immunol Rev. 1988 Jan;101:149–172. [PubMed]
  • Iwamoto A, Ohashi PS, Pircher H, Walker CL, Michalopoulos EE, Rupp F, Hengartner H, Mak TW. T cell receptor variable gene usage in a specific cytotoxic T cell response. Primary structure of the antigen-MHC receptor of four hapten-specific cytotoxic T cell clones. J Exp Med. 1987 Mar 1;165(3):591–600. [PMC free article] [PubMed]
  • Kronenberg M, Siu G, Hood LE, Shastri N. The molecular genetics of the T-cell antigen receptor and T-cell antigen recognition. Annu Rev Immunol. 1986;4:529–591. [PubMed]
  • Urban JL, Kumar V, Kono DH, Gomez C, Horvath SJ, Clayton J, Ando DG, Sercarz EE, 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. [PubMed]
  • Hedrick SM, Engel I, McElligott DL, Fink PJ, Hsu ML, Hansburg D, Matis LA. Selection of amino acid sequences in the beta chain of the T cell antigen receptor. Science. 1988 Mar 25;239(4847):1541–1544. [PubMed]
  • Engel I, Hedrick SM. 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. [PubMed]

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