Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Oct 1;180(4):1471–1483. doi: 10.1084/jem.180.4.1471

Determinant selection of major histocompatibility complex class I- restricted antigenic peptides is explained by class I-peptide affinity and is strongly influenced by nondominant anchor residues

PMCID: PMC2191679  PMID: 7523572

Abstract

The contribution of major histocompatibility complex (MHC) class I- peptide affinity to immunodominance of particular peptide antigens (Ags) in the class I-restricted cytotoxic T lymphocyte (CTL) response is not clearly established. Therefore, we have compared the H-2Kb- restricted binding and presentation of the immunodominant ovalbumin (OVA)257-264 (SIINFEKL) determinant to that of a subdominant OVA determinant OVA55-62 (KVVRFDKL). Immunodominance of OVA257-264 was not attributable to the specific T cell repertoire but correlated instead with more efficient Ag presentation. This enhanced Ag presentation could be accounted for by the higher affinity of Kb/OVA257-264 compared with Kb/OVA55-62 despite the presence of a conserved Kb-binding motif in both peptides. Kinetic binding studies using purified soluble H-2Kb molecules (Kbs) and biosensor techniques indicated that the Kon for association of OVA257-264-C6 and Kbs at 25 degrees C was integral of 10- fold faster (5.9 x 10(3) M-1 s-1 versus 6.5 x 10(2) M-1 s-1), and the Koff approximately twofold slower (9.1 x 10(-6) s-1 versus 1.6 x 10(-5) s-1), than the rate constants for interaction of OVA55-62-C6 and Kbs. The association of these peptides with Kb was significantly influenced by multiple residues at presumed nonanchor sites within the peptide sequence. The contribution of each peptide residue to Kb-binding was dependent upon the sequence context and the summed contributions were not additive. Thus the affinity of MHC class I-peptide binding is a critical factor controlling presentation of peptide Ag and immunodominance in the class I-restricted CTL response.

Full Text

The Full Text of this article is available as a PDF (1.4 MB).

Selected References

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

  1. Adorini L., Appella E., Doria G., Nagy Z. A. Mechanisms influencing the immunodominance of T cell determinants. J Exp Med. 1988 Dec 1;168(6):2091–2104. doi: 10.1084/jem.168.6.2091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ahluwalia N., Bergeron J. J., Wada I., Degen E., Williams D. B. The p88 molecular chaperone is identical to the endoplasmic reticulum membrane protein, calnexin. J Biol Chem. 1992 May 25;267(15):10914–10918. [PubMed] [Google Scholar]
  3. Bennink J. R., Yewdell J. W. Murine cytotoxic T lymphocyte recognition of individual influenza virus proteins. High frequency of nonresponder MHC class I alleles. J Exp Med. 1988 Nov 1;168(5):1935–1939. doi: 10.1084/jem.168.5.1935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bennink J. R., Yewdell J. W., Smith G. L., Moss B. Recognition of cloned influenza virus hemagglutinin gene products by cytotoxic T lymphocytes. J Virol. 1986 Mar;57(3):786–791. doi: 10.1128/jvi.57.3.786-791.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bluestone J. A., Jameson S., Miller S., Dick R., 2nd Peptide-induced conformational changes in class I heavy chains alter major histocompatibility complex recognition. J Exp Med. 1992 Dec 1;176(6):1757–1761. doi: 10.1084/jem.176.6.1757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Boehncke W. H., Takeshita T., Pendleton C. D., Houghten R. A., Sadegh-Nasseri S., Racioppi L., Berzofsky J. A., Germain R. N. The importance of dominant negative effects of amino acid side chain substitution in peptide-MHC molecule interactions and T cell recognition. J Immunol. 1993 Jan 15;150(2):331–341. [PubMed] [Google Scholar]
  7. Burgert H. G., White J., Weltzien H. U., Marrack P., Kappler J. W. Reactivity of V beta 17a+ CD8+ T cell hybrids. Analysis using a new CD8+ T cell fusion partner. J Exp Med. 1989 Dec 1;170(6):1887–1904. doi: 10.1084/jem.170.6.1887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Buus S., Sette A., Colon S. M., Miles C., Grey H. M. The relation between major histocompatibility complex (MHC) restriction and the capacity of Ia to bind immunogenic peptides. Science. 1987 Mar 13;235(4794):1353–1358. doi: 10.1126/science.2435001. [DOI] [PubMed] [Google Scholar]
  9. Carbone F. R., Bevan M. J. Class I-restricted processing and presentation of exogenous cell-associated antigen in vivo. J Exp Med. 1990 Feb 1;171(2):377–387. doi: 10.1084/jem.171.2.377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Carbone F. R., Sterry S. J., Butler J., Rodda S., Moore M. W. T cell receptor alpha-chain pairing determines the specificity of residue 262 within the Kb-restricted, ovalbumin257-264 determinant. Int Immunol. 1992 Aug;4(8):861–867. doi: 10.1093/intimm/4.8.861. [DOI] [PubMed] [Google Scholar]
  11. Catipović B., Dal Porto J., Mage M., Johansen T. E., Schneck J. P. Major histocompatibility complex conformational epitopes are peptide specific. J Exp Med. 1992 Dec 1;176(6):1611–1618. doi: 10.1084/jem.176.6.1611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cerundolo V., Elliott T., Elvin J., Bastin J., Rammensee H. G., Townsend A. The binding affinity and dissociation rates of peptides for class I major histocompatibility complex molecules. Eur J Immunol. 1991 Sep;21(9):2069–2075. doi: 10.1002/eji.1830210915. [DOI] [PubMed] [Google Scholar]
  13. Chen B. P., Parham P. Direct binding of influenza peptides to class I HLA molecules. Nature. 1989 Feb 23;337(6209):743–745. doi: 10.1038/337743a0. [DOI] [PubMed] [Google Scholar]
  14. Chen W., McCluskey J., Rodda S., Carbone F. R. Changes at peptide residues buried in the major histocompatibility complex (MHC) class I binding cleft influence T cell recognition: a possible role for indirect conformational alterations in the MHC class I or bound peptide in determining T cell recognition. J Exp Med. 1993 Mar 1;177(3):869–873. doi: 10.1084/jem.177.3.869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Choppin J., Martinon F., Gomard E., Bahraoui E., Connan F., Bouillot M., Lévy J. P. Analysis of physical interactions between peptides and HLA molecules and application to the detection of human immunodeficiency virus 1 antigenic peptides. J Exp Med. 1990 Sep 1;172(3):889–899. doi: 10.1084/jem.172.3.889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Corr M., Boyd L. F., Frankel S. R., Kozlowski S., Padlan E. A., Margulies D. H. Endogenous peptides of a soluble major histocompatibility complex class I molecule, H-2Lds: sequence motif, quantitative binding, and molecular modeling of the complex. J Exp Med. 1992 Dec 1;176(6):1681–1692. doi: 10.1084/jem.176.6.1681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Degen E., Cohen-Doyle M. F., Williams D. B. Efficient dissociation of the p88 chaperone from major histocompatibility complex class I molecules requires both beta 2-microglobulin and peptide. J Exp Med. 1992 Jun 1;175(6):1653–1661. doi: 10.1084/jem.175.6.1653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Deres K., Schumacher T. N., Wiesmüller K. H., Stevanović S., Greiner G., Jung G., Ploegh H. L. Preferred size of peptides that bind to H-2 Kb is sequence dependent. Eur J Immunol. 1992 Jun;22(6):1603–1608. doi: 10.1002/eji.1830220638. [DOI] [PubMed] [Google Scholar]
  19. Deverson E. V., Gow I. R., Coadwell W. J., Monaco J. J., Butcher G. W., Howard J. C. MHC class II region encoding proteins related to the multidrug resistance family of transmembrane transporters. Nature. 1990 Dec 20;348(6303):738–741. doi: 10.1038/348738a0. [DOI] [PubMed] [Google Scholar]
  20. Driscoll J., Brown M. G., Finley D., Monaco J. J. MHC-linked LMP gene products specifically alter peptidase activities of the proteasome. Nature. 1993 Sep 16;365(6443):262–264. doi: 10.1038/365262a0. [DOI] [PubMed] [Google Scholar]
  21. Falk K., Rötzschke O., Stevanović S., Jung G., Rammensee H. G. Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature. 1991 May 23;351(6324):290–296. doi: 10.1038/351290a0. [DOI] [PubMed] [Google Scholar]
  22. Frelinger J. A., Gotch F. M., Zweerink H., Wain E., McMichael A. J. Evidence of widespread binding of HLA class I molecules to peptides. J Exp Med. 1990 Sep 1;172(3):827–834. doi: 10.1084/jem.172.3.827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Fremont D. H., Matsumura M., Stura E. A., Peterson P. A., Wilson I. A. Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb. Science. 1992 Aug 14;257(5072):919–927. doi: 10.1126/science.1323877. [DOI] [PubMed] [Google Scholar]
  24. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  25. Guo H. C., Jardetzky T. S., Garrett T. P., Lane W. S., Strominger J. L., Wiley D. C. Different length peptides bind to HLA-Aw68 similarly at their ends but bulge out in the middle. Nature. 1992 Nov 26;360(6402):364–366. doi: 10.1038/360364a0. [DOI] [PubMed] [Google Scholar]
  26. Harding C. V., 3rd Electroporation of exogenous antigen into the cytosol for antigen processing and class I major histocompatibility complex (MHC) presentation: weak base amines and hypothermia (18 degrees C) inhibit the class I MHC processing pathway. Eur J Immunol. 1992 Jul;22(7):1865–1869. doi: 10.1002/eji.1830220728. [DOI] [PubMed] [Google Scholar]
  27. Hogquist K. A., Grandea A. G., 3rd, Bevan M. J. Peptide variants reveal how antibodies recognize major histocompatibility complex class I. Eur J Immunol. 1993 Nov;23(11):3028–3036. doi: 10.1002/eji.1830231145. [DOI] [PubMed] [Google Scholar]
  28. Jameson S. C., Bevan M. J. Dissection of major histocompatibility complex (MHC) and T cell receptor contact residues in a Kb-restricted ovalbumin peptide and an assessment of the predictive power of MHC-binding motifs. Eur J Immunol. 1992 Oct;22(10):2663–2667. doi: 10.1002/eji.1830221028. [DOI] [PubMed] [Google Scholar]
  29. Jardetzky T. S., Lane W. S., Robinson R. A., Madden D. R., Wiley D. C. Identification of self peptides bound to purified HLA-B27. Nature. 1991 Sep 26;353(6342):326–329. doi: 10.1038/353326a0. [DOI] [PubMed] [Google Scholar]
  30. Jönsson U., Fägerstam L., Ivarsson B., Johnsson B., Karlsson R., Lundh K., Löfås S., Persson B., Roos H., Rönnberg I. Real-time biospecific interaction analysis using surface plasmon resonance and a sensor chip technology. Biotechniques. 1991 Nov;11(5):620–627. [PubMed] [Google Scholar]
  31. Kelly A., Powis S. H., Kerr L. A., Mockridge I., Elliott T., Bastin J., Uchanska-Ziegler B., Ziegler A., Trowsdale J., Townsend A. Assembly and function of the two ABC transporter proteins encoded in the human major histocompatibility complex. Nature. 1992 Feb 13;355(6361):641–644. doi: 10.1038/355641a0. [DOI] [PubMed] [Google Scholar]
  32. Khilko S. N., Corr M., Boyd L. F., Lees A., Inman J. K., Margulies D. H. Direct detection of major histocompatibility complex class I binding to antigenic peptides using surface plasmon resonance. Peptide immobilization and characterization of binding specificity. J Biol Chem. 1993 Jul 25;268(21):15425–15434. [PubMed] [Google Scholar]
  33. Kleijmeer M. J., Kelly A., Geuze H. J., Slot J. W., Townsend A., Trowsdale J. Location of MHC-encoded transporters in the endoplasmic reticulum and cis-Golgi. Nature. 1992 May 28;357(6376):342–344. doi: 10.1038/357342a0. [DOI] [PubMed] [Google Scholar]
  34. Kärre K., Ljunggren H. G., Piontek G., Kiessling R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature. 1986 Feb 20;319(6055):675–678. doi: 10.1038/319675a0. [DOI] [PubMed] [Google Scholar]
  35. Lipford G. B., Hoffman M., Wagner H., Heeg K. Primary in vivo responses to ovalbumin. Probing the predictive value of the Kb binding motif. J Immunol. 1993 Feb 15;150(4):1212–1222. [PubMed] [Google Scholar]
  36. Ljunggren H. G., Stam N. J., Ohlén C., Neefjes J. J., Höglund P., Heemels M. T., Bastin J., Schumacher T. N., Townsend A., Kärre K. Empty MHC class I molecules come out in the cold. Nature. 1990 Aug 2;346(6283):476–480. doi: 10.1038/346476a0. [DOI] [PubMed] [Google Scholar]
  37. Mamula M. J. The inability to process a self-peptide allows autoreactive T cells to escape tolerance. J Exp Med. 1993 Feb 1;177(2):567–571. doi: 10.1084/jem.177.2.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Margulies D. H., Corr M., Boyd L. F., Khilko S. N. MHC class I/peptide interactions: binding specificity and kinetics. J Mol Recognit. 1993 Jun;6(2):59–69. doi: 10.1002/jmr.300060204. [DOI] [PubMed] [Google Scholar]
  39. Maryanski J. L., Abastado J. P., Kourilsky P. Specificity of peptide presentation by a set of hybrid mouse class I MHC molecules. Nature. 1987 Dec 17;330(6149):660–662. doi: 10.1038/330660a0. [DOI] [PubMed] [Google Scholar]
  40. Matsumura M., Fremont D. H., Peterson P. A., Wilson I. A. Emerging principles for the recognition of peptide antigens by MHC class I molecules. Science. 1992 Aug 14;257(5072):927–934. doi: 10.1126/science.1323878. [DOI] [PubMed] [Google Scholar]
  41. Matsumura M., Saito Y., Jackson M. R., Song E. S., Peterson P. A. In vitro peptide binding to soluble empty class I major histocompatibility complex molecules isolated from transfected Drosophila melanogaster cells. J Biol Chem. 1992 Nov 25;267(33):23589–23595. [PubMed] [Google Scholar]
  42. Moore M. W., Carbone F. R., Bevan M. J. Introduction of soluble protein into the class I pathway of antigen processing and presentation. Cell. 1988 Sep 9;54(6):777–785. doi: 10.1016/s0092-8674(88)91043-4. [DOI] [PubMed] [Google Scholar]
  43. Neefjes J. J., Momburg F., Hämmerling G. J. Selective and ATP-dependent translocation of peptides by the MHC-encoded transporter. Science. 1993 Aug 6;261(5122):769–771. doi: 10.1126/science.8342042. [DOI] [PubMed] [Google Scholar]
  44. Nikolić-Zugić J., Carbone F. R. The effect of mutations in the MHC class I peptide binding groove on the cytotoxic T lymphocyte recognition of the Kb-restricted ovalbumin determinant. Eur J Immunol. 1990 Nov;20(11):2431–2437. doi: 10.1002/eji.1830201111. [DOI] [PubMed] [Google Scholar]
  45. Nuchtern J. G., Bonifacino J. S., Biddison W. E., Klausner R. D. Brefeldin A implicates egress from endoplasmic reticulum in class I restricted antigen presentation. Nature. 1989 May 18;339(6221):223–226. doi: 10.1038/339223a0. [DOI] [PubMed] [Google Scholar]
  46. Ojcius D. M., Abastado J. P., Casrouge A., Mottez E., Cabanie L., Kourilsky P. Dissociation of the peptide-MHC class I complex limits the binding rate of exogenous peptide. J Immunol. 1993 Dec 1;151(11):6020–6026. [PubMed] [Google Scholar]
  47. Ojcius D. M., Godeau F., Abastado J. P., Casanova J. L., Kourilsky P. Real-time measurement of antigenic peptide binding to empty and preloaded single-chain major histocompatibility complex class I molecules. Eur J Immunol. 1993 May;23(5):1118–1124. doi: 10.1002/eji.1830230521. [DOI] [PubMed] [Google Scholar]
  48. Otten G. R., Bikoff E., Ribaudo R. K., Kozlowski S., Margulies D. H., Germain R. N. Peptide and beta 2-microglobulin regulation of cell surface MHC class I conformation and expression. J Immunol. 1992 Jun 15;148(12):3723–3732. [PubMed] [Google Scholar]
  49. Pamer E. G., Harty J. T., Bevan M. J. Precise prediction of a dominant class I MHC-restricted epitope of Listeria monocytogenes. Nature. 1991 Oct 31;353(6347):852–855. doi: 10.1038/353852a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Parker K. C., Bednarek M. A., Coligan J. E. Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol. 1994 Jan 1;152(1):163–175. [PubMed] [Google Scholar]
  51. Powis S. J., Townsend A. R., Deverson E. V., Bastin J., Butcher G. W., Howard J. C. Restoration of antigen presentation to the mutant cell line RMA-S by an MHC-linked transporter. Nature. 1991 Dec 19;354(6354):528–531. doi: 10.1038/354528a0. [DOI] [PubMed] [Google Scholar]
  52. Rock K. L., Rothstein L., Gamble S., Gramm C., Benacerraf B. Chemical cross-linking of class I molecules on cells creates receptive peptide binding sites. J Immunol. 1992 Mar 1;148(5):1451–1457. [PubMed] [Google Scholar]
  53. Ruppert J., Sidney J., Celis E., Kubo R. T., Grey H. M., Sette A. Prominent role of secondary anchor residues in peptide binding to HLA-A2.1 molecules. Cell. 1993 Sep 10;74(5):929–937. doi: 10.1016/0092-8674(93)90472-3. [DOI] [PubMed] [Google Scholar]
  54. Rötzschke O., Falk K., Stevanović S., Jung G., Walden P., Rammensee H. G. Exact prediction of a natural T cell epitope. Eur J Immunol. 1991 Nov;21(11):2891–2894. doi: 10.1002/eji.1830211136. [DOI] [PubMed] [Google Scholar]
  55. Saito Y., Peterson P. A., Matsumura M. Quantitation of peptide anchor residue contributions to class I major histocompatibility complex molecule binding. J Biol Chem. 1993 Oct 5;268(28):21309–21317. [PubMed] [Google Scholar]
  56. Saper M. A., Bjorkman P. J., Wiley D. C. Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 A resolution. J Mol Biol. 1991 May 20;219(2):277–319. doi: 10.1016/0022-2836(91)90567-p. [DOI] [PubMed] [Google Scholar]
  57. Schaeffer E. B., Sette A., Johnson D. L., Bekoff M. C., Smith J. A., Grey H. M., Buus S. Relative contribution of "determinant selection" and "holes in the T-cell repertoire" to T-cell responses. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4649–4653. doi: 10.1073/pnas.86.12.4649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Schneck J., Maloy W. L., Coligan J. E., Margulies D. H. Inhibition of an allospecific T cell hybridoma by soluble class I proteins and peptides: estimation of the affinity of a T cell receptor for MHC. Cell. 1989 Jan 13;56(1):47–55. doi: 10.1016/0092-8674(89)90982-3. [DOI] [PubMed] [Google Scholar]
  59. Sette A., Sidney J., Gaeta F. C., Appella E., Colón S. M., del Guercio M. F., Guéry J. C., Adorini L. MHC class II molecules bind indiscriminately self and non-self peptide homologs: effect on the immunogenicity of non-self peptides. Int Immunol. 1993 Jun;5(6):631–638. doi: 10.1093/intimm/5.6.631. [DOI] [PubMed] [Google Scholar]
  60. Shepherd J. C., Schumacher T. N., Ashton-Rickardt P. G., Imaeda S., Ploegh H. L., Janeway C. A., Jr, Tonegawa S. TAP1-dependent peptide translocation in vitro is ATP dependent and peptide selective. Cell. 1993 Aug 13;74(3):577–584. doi: 10.1016/0092-8674(93)80058-m. [DOI] [PubMed] [Google Scholar]
  61. Takahashi H., Cohen J., Hosmalin A., Cease K. B., Houghten R., Cornette J. L., DeLisi C., Moss B., Germain R. N., Berzofsky J. A. An immunodominant epitope of the human immunodeficiency virus envelope glycoprotein gp160 recognized by class I major histocompatibility complex molecule-restricted murine cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1988 May;85(9):3105–3109. doi: 10.1073/pnas.85.9.3105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Townsend A., Elliott T., Cerundolo V., Foster L., Barber B., Tse A. Assembly of MHC class I molecules analyzed in vitro. Cell. 1990 Jul 27;62(2):285–295. doi: 10.1016/0092-8674(90)90366-m. [DOI] [PubMed] [Google Scholar]
  63. Wettstein P. J., van Bleek G. M., Nathenson S. G. Differential binding of a minor histocompatibility antigen peptide to H-2 class I molecules correlates with immune responsiveness. J Immunol. 1993 Apr 1;150(7):2753–2760. [PubMed] [Google Scholar]
  64. Yokota S., Lafuse W. P., McCormick J. F., David C. S. Detection of hybrid (combinatorial) Ia antigens using parent anti-F1 sera. J Immunol. 1981 Jan;126(1):371–374. [PubMed] [Google Scholar]
  65. van Bleek G. M., Nathenson S. G. The structure of the antigen-binding groove of major histocompatibility complex class I molecules determines specific selection of self-peptides. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11032–11036. doi: 10.1073/pnas.88.24.11032. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES