Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 May 1;181(5):1817–1825. doi: 10.1084/jem.181.5.1817

H-2M3a violates the paradigm for major histocompatibility complex class I peptide binding

PMCID: PMC2191989  PMID: 7722457

Abstract

The major histocompatibility (MHC) class I-b molecule H-2M3a binds and presents N-formylated peptides to cytotoxic T lymphocytes. This requirement potentially places severe constraints on the number of peptides that M3a can present to the immune system. Consistent with this idea, the M3a-Ld MHC class I chimera is expressed at very low levels on the cell surface, but can be induced significantly by the addition of specific peptides at 27 degrees C. Using this assay, we show that M3a binds many very short N-formyl peptides, including N- formyl chemotactic peptides and canonical octapeptides. This observation is in sharp contrast to the paradigmatic size range of peptides of 8-10 amino acids binding to most class I-a molecules and the class I-b molecule Qa-2. Stabilization by fMLF-benzyl amide could be detected at peptide concentrations as low as 100 nM. While N-formyl peptides as short as two amino acids in length stabilized expression of M3a-Ld, increasing the length of these peptides added to the stability of peptide-MHC complexes as determined by 27-37 degrees C temperature shift experiments. We propose that relaxation of the length rule may represent a compensatory adaptation to maximize the number of peptides that can be presented by H-2M3a.

Full Text

The Full Text of this article is available as a PDF (875.7 KB).

Selected References

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

  1. Ashton-Rickardt P. G., Van Kaer L., Schumacher T. N., Ploegh H. L., Tonegawa S. Peptide contributes to the specificity of positive selection of CD8+ T cells in the thymus. Cell. 1993 Jun 4;73(5):1041–1049. doi: 10.1016/0092-8674(93)90281-t. [DOI] [PubMed] [Google Scholar]
  2. Balk S. P., Burke S., Polischuk J. E., Frantz M. E., Yang L., Porcelli S., Colgan S. P., Blumberg R. S. Beta 2-microglobulin-independent MHC class Ib molecule expressed by human intestinal epithelium. Science. 1994 Jul 8;265(5169):259–262. doi: 10.1126/science.7517575. [DOI] [PubMed] [Google Scholar]
  3. Bibb M. J., Van Etten R. A., Wright C. T., Walberg M. W., Clayton D. A. Sequence and gene organization of mouse mitochondrial DNA. Cell. 1981 Oct;26(2 Pt 2):167–180. doi: 10.1016/0092-8674(81)90300-7. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Carbone F. R., Bevan M. J. Induction of ovalbumin-specific cytotoxic T cells by in vivo peptide immunization. J Exp Med. 1989 Mar 1;169(3):603–612. doi: 10.1084/jem.169.3.603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Freer R. J., Day A. R., Muthukumaraswamy N., Pinon D., Wu A., Showell H. J., Becker E. L. Formyl peptide chemoattractants: a model of the receptor on rabbit neutrophils. Biochemistry. 1982 Jan 19;21(2):257–263. doi: 10.1021/bi00531a009. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Germain R. N., Margulies D. H. The biochemistry and cell biology of antigen processing and presentation. Annu Rev Immunol. 1993;11:403–450. doi: 10.1146/annurev.iy.11.040193.002155. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Henderson R. A., Michel H., Sakaguchi K., Shabanowitz J., Appella E., Hunt D. F., Engelhard V. H. HLA-A2.1-associated peptides from a mutant cell line: a second pathway of antigen presentation. Science. 1992 Mar 6;255(5049):1264–1266. doi: 10.1126/science.1546329. [DOI] [PubMed] [Google Scholar]
  11. Hershberg R., Eghtesady P., Sydora B., Brorson K., Cheroutre H., Modlin R., Kronenberg M. Expression of the thymus leukemia antigen in mouse intestinal epithelium. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9727–9731. doi: 10.1073/pnas.87.24.9727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hogquist K. A., Jameson S. C., Heath W. R., Howard J. L., Bevan M. J., Carbone F. R. T cell receptor antagonist peptides induce positive selection. Cell. 1994 Jan 14;76(1):17–27. doi: 10.1016/0092-8674(94)90169-4. [DOI] [PubMed] [Google Scholar]
  13. Joyce S., Kuzushima K., Kepecs G., Angeletti R. H., Nathenson S. G. Characterization of an incompletely assembled major histocompatibility class I molecule (H-2Kb) associated with unusually long peptides: implications for antigen processing and presentation. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4145–4149. doi: 10.1073/pnas.91.10.4145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Joyce S., Tabaczewski P., Angeletti R. H., Nathenson S. G., Stroynowski I. A nonpolymorphic major histocompatibility complex class Ib molecule binds a large array of diverse self-peptides. J Exp Med. 1994 Feb 1;179(2):579–588. doi: 10.1084/jem.179.2.579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kurlander R. J., Shawar S. M., Brown M. L., Rich R. R. Specialized role for a murine class I-b MHC molecule in prokaryotic host defenses. Science. 1992 Jul 31;257(5070):678–679. doi: 10.1126/science.1496381. [DOI] [PubMed] [Google Scholar]
  16. Latron F., Pazmany L., Morrison J., Moots R., Saper M. A., McMichael A., Strominger J. L. A critical role for conserved residues in the cleft of HLA-A2 in presentation of a nonapeptide to T cells. Science. 1992 Aug 14;257(5072):964–967. doi: 10.1126/science.1380181. [DOI] [PubMed] [Google Scholar]
  17. Lloyd E. A., Gould S. J. Species selection on variability. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):595–599. doi: 10.1073/pnas.90.2.595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Loveland B., Wang C. R., Yonekawa H., Hermel E., Lindahl K. F. Maternally transmitted histocompatibility antigen of mice: a hydrophobic peptide of a mitochondrially encoded protein. Cell. 1990 Mar 23;60(6):971–980. doi: 10.1016/0092-8674(90)90345-f. [DOI] [PubMed] [Google Scholar]
  19. Madden D. R., Garboczi D. N., Wiley D. C. The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2. Cell. 1993 Nov 19;75(4):693–708. doi: 10.1016/0092-8674(93)90490-h. [DOI] [PubMed] [Google Scholar]
  20. Madden D. R., Gorga J. C., Strominger J. L., Wiley D. C. The three-dimensional structure of HLA-B27 at 2.1 A resolution suggests a general mechanism for tight peptide binding to MHC. Cell. 1992 Sep 18;70(6):1035–1048. doi: 10.1016/0092-8674(92)90252-8. [DOI] [PubMed] [Google Scholar]
  21. Matsui M., Hioe C. E., Frelinger J. A. Roles of the six peptide-binding pockets of the HLA-A2 molecule in allorecognition by human cytotoxic T-cell clones. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):674–678. doi: 10.1073/pnas.90.2.674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Morrison J., Elvin J., Latron F., Gotch F., Moots R., Strominger J. L., McMichael A. Identification of the nonamer peptide from influenza A matrix protein and the role of pockets of HLA-A2 in its recognition by cytotoxic T lymphocytes. Eur J Immunol. 1992 Apr;22(4):903–907. doi: 10.1002/eji.1830220404. [DOI] [PubMed] [Google Scholar]
  23. Murphy P. M. The molecular biology of leukocyte chemoattractant receptors. Annu Rev Immunol. 1994;12:593–633. doi: 10.1146/annurev.iy.12.040194.003113. [DOI] [PubMed] [Google Scholar]
  24. Ozato K., Hansen T. H., Sachs D. H. Monoclonal antibodies to mouse MHC antigens. II. Antibodies to the H-2Ld antigen, the products of a third polymorphic locus of the mouse major histocompatibility complex. J Immunol. 1980 Dec;125(6):2473–2477. [PubMed] [Google Scholar]
  25. Ozato K., Sachs D. H. Monoclonal antibodies to mouse MHC antigens. III. Hybridoma antibodies reacting to antigens of the H-2b haplotype reveal genetic control of isotype expression. J Immunol. 1981 Jan;126(1):317–321. [PubMed] [Google Scholar]
  26. Pamer E. G., Bevan M. J., Lindahl K. F. Do nonclassical, class Ib MHC molecules present bacterial antigens to T cells? Trends Microbiol. 1993 Apr;1(1):35–38. doi: 10.1016/0966-842x(93)90023-k. [DOI] [PubMed] [Google Scholar]
  27. Pamer E. G., Wang C. R., Flaherty L., Lindahl K. F., Bevan M. J. H-2M3 presents a Listeria monocytogenes peptide to cytotoxic T lymphocytes. Cell. 1992 Jul 24;70(2):215–223. doi: 10.1016/0092-8674(92)90097-v. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Rammensee H. G., Falk K., Rötzschke O. Peptides naturally presented by MHC class I molecules. Annu Rev Immunol. 1993;11:213–244. doi: 10.1146/annurev.iy.11.040193.001241. [DOI] [PubMed] [Google Scholar]
  30. Rammensee H. G., Rötzschke O., Falk K. MHC class I-restricted antigen processing--lessons from natural ligands. Chem Immunol. 1993;57:113–133. doi: 10.1159/000319185. [DOI] [PubMed] [Google Scholar]
  31. Reddehase M. J., Rothbard J. B., Koszinowski U. H. A pentapeptide as minimal antigenic determinant for MHC class I-restricted T lymphocytes. Nature. 1989 Feb 16;337(6208):651–653. doi: 10.1038/337651a0. [DOI] [PubMed] [Google Scholar]
  32. Rock K. L., Gramm C., Benacerraf B. Low temperature and peptides favor the formation of class I heterodimers on RMA-S cells at the cell surface. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4200–4204. doi: 10.1073/pnas.88.10.4200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rodgers J. R., Johnson M. L., Rosen J. M. Measurement of mRNA concentration and mRNA half-life as a function of hormonal treatment. Methods Enzymol. 1985;109:572–592. doi: 10.1016/0076-6879(85)09116-9. [DOI] [PubMed] [Google Scholar]
  34. Rodgers J. R., Shawar S. M., Guenther M. M., Rich R. R. Kinetics of killing by monoclonal cytotoxic T lymphocytes. I. Colorimetric detection of cryptic CTL determinants on adherent target cells and survivorship analysis. J Immunol Methods. 1992 Aug 10;152(2):159–169. doi: 10.1016/0022-1759(92)90137-i. [DOI] [PubMed] [Google Scholar]
  35. Rodgers J. R., Wyde P. R., Rich R. R. Mutational analysis of regulation of MHC and anti-viral genes. J Immunol. 1991 Mar 15;146(6):1979–1986. [PubMed] [Google Scholar]
  36. Rötzschke O., Falk K., Stevanović S., Grahovac B., Soloski M. J., Jung G., Rammensee H. G. Qa-2 molecules are peptide receptors of higher stringency than ordinary class I molecules. Nature. 1993 Feb 18;361(6413):642–644. doi: 10.1038/361642a0. [DOI] [PubMed] [Google Scholar]
  37. 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]
  38. Schulz M., Aichele P., Schneider R., Hansen T. H., Zinkernagel R. M., Hengartner H. Major histocompatibility complex binding and T cell recognition of a viral nonapeptide containing a minimal tetrapeptide. Eur J Immunol. 1991 May;21(5):1181–1185. doi: 10.1002/eji.1830210513. [DOI] [PubMed] [Google Scholar]
  39. Schumacher T. N., De Bruijn M. L., Vernie L. N., Kast W. M., Melief C. J., Neefjes J. J., Ploegh H. L. Peptide selection by MHC class I molecules. Nature. 1991 Apr 25;350(6320):703–706. doi: 10.1038/350703a0. [DOI] [PubMed] [Google Scholar]
  40. Shawar S. M., Cook R. G., Rodgers J. R., Rich R. R. Specialized functions of MHC class I molecules. I. An N-formyl peptide receptor is required for construction of the class I antigen Mta. J Exp Med. 1990 Mar 1;171(3):897–912. doi: 10.1084/jem.171.3.897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Shawar S. M., Vyas J. M., Rodgers J. R., Cook R. G., Rich R. R. Specialized functions of major histocompatibility complex class I molecules. II. Hmt binds N-formylated peptides of mitochondrial and prokaryotic origin. J Exp Med. 1991 Oct 1;174(4):941–944. doi: 10.1084/jem.174.4.941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Shawar S. M., Vyas J. M., Rodgers J. R., Rich R. R. Antigen presentation by major histocompatibility complex class I-B molecules. Annu Rev Immunol. 1994;12:839–880. doi: 10.1146/annurev.iy.12.040194.004203. [DOI] [PubMed] [Google Scholar]
  43. Shawar S. M., Vyas J. M., Shen E., Rodgers J. R., Rich R. R. Differential amino-terminal anchors for peptide binding to H-2M3a or H-2Kb and H-2Db. J Immunol. 1993 Jul 1;151(1):201–210. [PubMed] [Google Scholar]
  44. Urban R. G., Chicz R. M., Lane W. S., Strominger J. L., Rehm A., Kenter M. J., UytdeHaag F. G., Ploegh H., Uchanska-Ziegler B., Ziegler A. A subset of HLA-B27 molecules contains peptides much longer than nonamers. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1534–1538. doi: 10.1073/pnas.91.4.1534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Villadangos J. A., Galocha B., López de Castro J. A. Unusual topology of an HLA-B27 allospecific T cell epitope lacking peptide specificity. J Immunol. 1994 Mar 1;152(5):2317–2323. [PubMed] [Google Scholar]
  46. Vyas J. M., Rich R. R., Howell D. D., Shawar S. M., Rodgers J. R. Availability of endogenous peptides limits expression of an M3a-Ld major histocompatibility complex class I chimera. J Exp Med. 1994 Jan 1;179(1):155–165. doi: 10.1084/jem.179.1.155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Vyas J. M., Shawar S. M., Rodgers J. R., Cook R. G., Rich R. R. Biochemical specificity of H-2M3a. Stereospecificity and space-filling requirements at position 1 maintain N-formyl peptide binding. J Immunol. 1992 Dec 1;149(11):3605–3611. [PubMed] [Google Scholar]
  48. Wipke B. T., Jameson S. C., Bevan M. J., Pamer E. G. Variable binding affinities of listeriolysin O peptides for the H-2Kd class I molecule. Eur J Immunol. 1993 Aug;23(8):2005–2010. doi: 10.1002/eji.1830230842. [DOI] [PubMed] [Google Scholar]
  49. de la Salle H., Hanau D., Fricker D., Urlacher A., Kelly A., Salamero J., Powis S. H., Donato L., Bausinger H., Laforet M. Homozygous human TAP peptide transporter mutation in HLA class I deficiency. Science. 1994 Jul 8;265(5169):237–241. doi: 10.1126/science.7517574. [DOI] [PubMed] [Google Scholar]

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

RESOURCES