Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Dec 1;178(6):2131–2138. doi: 10.1084/jem.178.6.2131

Dominant determinants in hen eggwhite lysozyme correspond to the cryptic determinants within its self-homologue, mouse lysozyme: implications in shaping of the T cell repertoire and autoimmunity

PMCID: PMC2191305  PMID: 8245785

Abstract

We have studied the mouse lysozyme (ML) peptide-specific T cell repertoire in mice of five different major histocompatibility complex (MHC) class II haplotypes. 14 ML peptides were tested in a lymph node T cell proliferation assay. Upon immunization of diverse mouse strains with native ML, there was no response to any of the ML peptides tested. However, nine peptides were immunogenic, although there was no consistent pattern of reactivity toward any peptide among these strains. Thus, an autoreactive T cell repertoire directed against cryptic self(ML)-determinants exists, and it is different in mice of different MHC haplotypes. Moreover, our results demonstrate that crypticity is MHC associated and not merely a structural attribute of the determinant. On comparison of the pattern of response of various peptides of ML and that of its foreign homologue, hen eggwhite lysozyme (HEL) in H-2k, H-2b, and H-2d strains of mice, a striking correlation was evident. The stretches of amino acid sequences of determinants within HEL that were dominant in each of these three strains, almost exactly overlapped in position with those of the cryptic ML determinants against which self-reactivity was demonstrated in the same strain. These results demonstrate that the dominance-crypticity relationship between HEL and ML resulting from differential processing of these two proteins is critical in determining the response to HEL rather than the degree of sequence difference between them. These observations have important implications in the shaping of the T cell repertoire for foreign proteins and in the pathogenesis of autoimmunity.

Full Text

The Full Text of this article is available as a PDF (919.1 KB).

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. Agrawal B., Manickasundari M., Fraga E., Singh B. T cells that recognize peptide sequences of self MHC class II molecules exist in syngeneic mice. J Immunol. 1991 Jul 15;147(2):383–390. [PubMed] [Google Scholar]
  3. Allen P. M., McKean D. J., Beck B. N., Sheffield J., Glimcher L. H. Direct evidence that a class II molecule and a simple globular protein generate multiple determinants. J Exp Med. 1985 Oct 1;162(4):1264–1274. doi: 10.1084/jem.162.4.1264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Benichou G., Takizawa P. A., Ho P. T., Killion C. C., Olson C. A., McMillan M., Sercarz E. E. Immunogenicity and tolerogenicity of self-major histocompatibility complex peptides. J Exp Med. 1990 Nov 1;172(5):1341–1346. doi: 10.1084/jem.172.5.1341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cohen S. A., Strydom D. J. Amino acid analysis utilizing phenylisothiocyanate derivatives. Anal Biochem. 1988 Oct;174(1):1–16. doi: 10.1016/0003-2697(88)90512-x. [DOI] [PubMed] [Google Scholar]
  6. Cross M., Mangelsdorf I., Wedel A., Renkawitz R. Mouse lysozyme M gene: isolation, characterization, and expression studies. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6232–6236. doi: 10.1073/pnas.85.17.6232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fowell D., Mason D. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J Exp Med. 1993 Mar 1;177(3):627–636. doi: 10.1084/jem.177.3.627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gammon G., Geysen H. M., Apple R. J., Pickett E., Palmer M., Ametani A., Sercarz E. E. T cell determinant structure: cores and determinant envelopes in three mouse major histocompatibility complex haplotypes. J Exp Med. 1991 Mar 1;173(3):609–617. doi: 10.1084/jem.173.3.609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gammon G., Klotz J., Ando D., Sercarz E. E. The T cell repertoire to a multideterminant antigen. Clonal heterogeneity of the T cell response, variation between syngeneic individuals, and in vitro selection of T cell specificities. J Immunol. 1990 Mar 1;144(5):1571–1577. [PubMed] [Google Scholar]
  10. Gammon G., Sercarz E. How some T cells escape tolerance induction. Nature. 1989 Nov 9;342(6246):183–185. doi: 10.1038/342183a0. [DOI] [PubMed] [Google Scholar]
  11. Gaston J. S., Life P. F., Jenner P. J., Colston M. J., Bacon P. A. Recognition of a mycobacteria-specific epitope in the 65-kD heat-shock protein by synovial fluid-derived T cell clones. J Exp Med. 1990 Mar 1;171(3):831–841. doi: 10.1084/jem.171.3.831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Henwood J., Loveridge J., Bell J. I., Gaston J. S. Restricted T cell receptor expression by human T cell clones specific for mycobacterial 65-kDa heat-shock protein: selective in vivo expansion of T cells bearing defined receptors. Eur J Immunol. 1993 Jun;23(6):1256–1265. doi: 10.1002/eji.1830230610. [DOI] [PubMed] [Google Scholar]
  13. Houghten R. A. General method for the rapid solid-phase synthesis of large numbers of peptides: specificity of antigen-antibody interaction at the level of individual amino acids. Proc Natl Acad Sci U S A. 1985 Aug;82(15):5131–5135. doi: 10.1073/pnas.82.15.5131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kappler J. W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. doi: 10.1016/0092-8674(87)90568-x. [DOI] [PubMed] [Google Scholar]
  15. Kisielow P., Blüthmann H., Staerz U. D., Steinmetz M., von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988 Jun 23;333(6175):742–746. doi: 10.1038/333742a0. [DOI] [PubMed] [Google Scholar]
  16. Lehmann P. V., Sercarz E. E., Forsthuber T., Dayan C. M., Gammon G. Determinant spreading and the dynamics of the autoimmune T-cell repertoire. Immunol Today. 1993 May;14(5):203–208. doi: 10.1016/0167-5699(93)90163-F. [DOI] [PubMed] [Google Scholar]
  17. Lin R. H., Mamula M. J., Hardin J. A., Janeway C. A., Jr Induction of autoreactive B cells allows priming of autoreactive T cells. J Exp Med. 1991 Jun 1;173(6):1433–1439. doi: 10.1084/jem.173.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Liu Z. R., Williams K. P., Chang Y. H., Smith J. A. Single amino acid substitution alters T cell determinant selection during antigen processing of Staphylococcus aureus nuclease. J Immunol. 1991 Jan 15;146(2):438–443. [PubMed] [Google Scholar]
  19. Lorenz R. G., Allen P. M. Direct evidence for functional self-protein/Ia-molecule complexes in vivo. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5220–5223. doi: 10.1073/pnas.85.14.5220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Oldstone M. B. Molecular mimicry as a mechanism for the cause and a probe uncovering etiologic agent(s) of autoimmune disease. Curr Top Microbiol Immunol. 1989;145:127–135. doi: 10.1007/978-3-642-74594-2_11. [DOI] [PubMed] [Google Scholar]
  22. PARRY R. M., Jr, CHANDAN R. C., SHAHANI K. M. A RAPID AND SENSITIVE ASSAY OF MURAMIDASE. Proc Soc Exp Biol Med. 1965 Jun;119:384–386. doi: 10.3181/00379727-119-30188. [DOI] [PubMed] [Google Scholar]
  23. Quayle A. J., Wilson K. B., Li S. G., Kjeldsen-Kragh J., Oftung F., Shinnick T., Sioud M., Førre O., Capra J. D., Natvig J. B. Peptide recognition, T cell receptor usage and HLA restriction elements of human heat-shock protein (hsp) 60 and mycobacterial 65-kDa hsp-reactive T cell clones from rheumatoid synovial fluid. Eur J Immunol. 1992 May;22(5):1315–1322. doi: 10.1002/eji.1830220529. [DOI] [PubMed] [Google Scholar]
  24. Riblet R. J., Herzenberg L. A. Mouse lysozyme production by a monocytoma: isolation and comparison with other lysozymes. Science. 1970 Jun 26;168(3939):1595–1597. doi: 10.1126/science.168.3939.1595. [DOI] [PubMed] [Google Scholar]
  25. Schönrich G., Kalinke U., Momburg F., Malissen M., Schmitt-Verhulst A. M., Malissen B., Hämmerling G. J., Arnold B. Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell. 1991 Apr 19;65(2):293–304. doi: 10.1016/0092-8674(91)90163-s. [DOI] [PubMed] [Google Scholar]
  26. Sette A., Buus S., Appella E., Smith J. A., Chesnut R., Miles C., Colon S. M., Grey H. M. Prediction of major histocompatibility complex binding regions of protein antigens by sequence pattern analysis. Proc Natl Acad Sci U S A. 1989 May;86(9):3296–3300. doi: 10.1073/pnas.86.9.3296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Stockinger B., Lin R. H. An intracellular self protein synthesized in macrophages is presented but fails to induce tolerance. Int Immunol. 1989;1(6):592–597. doi: 10.1093/intimm/1.6.592. [DOI] [PubMed] [Google Scholar]
  29. Takahama Y., Shores E. W., Singer A. Negative selection of precursor thymocytes before their differentiation into CD4+CD8+ cells. Science. 1992 Oct 23;258(5082):653–656. doi: 10.1126/science.1357752. [DOI] [PubMed] [Google Scholar]
  30. van Eden W., Thole J. E., van der Zee R., Noordzij A., van Embden J. D., Hensen E. J., Cohen I. R. Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature. 1988 Jan 14;331(6152):171–173. doi: 10.1038/331171a0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES