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. 1988 Jul;85(14):5220–5223. doi: 10.1073/pnas.85.14.5220

Direct evidence for functional self-protein/Ia-molecule complexes in vivo.

R G Lorenz 1, P M Allen 1
PMCID: PMC281720  PMID: 2839836

Abstract

Through the development of a panel of murine hybridomas reactive to murine hemoglobin, we have been able to study the processing and presentation of self antigens by antigen-presenting cells. Our results demonstrate that peritoneal macrophages in vivo can process and potentially present the self-antigen hemoglobin. We have extended this finding to show that, directly after removal from the mouse, antigen-presenting cells from a variety of tissues stimulate our hemoglobin-specific hybridomas without any manipulation or addition of exogenous antigen. This constitutes direct functional proof that in a nondisease state self proteins are processed constitutively and can be presented in a fashion similar to that in which foreign antigens are presented. Our demonstration that antigen-presenting cells can process and potentially present self as well as foreign molecules implies that self-tolerance occurs at the level of the T cell. This constitutive processing and presentation of self antigens has potentially far-reaching implications in self-tolerance, autoimmunity, and alloreactivity.

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Selected References

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

  1. Abromson-Leeman S. R., Cantor H. Specificity of T cell clones for antigen and autologous major histocompatibility complex products determines specificity for foreign major histocompatibility complex products. J Exp Med. 1983 Aug 1;158(2):428–437. doi: 10.1084/jem.158.2.428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Allen P. M., Beller D. I., Braun J., Unanue E. R. The handling of Listeria monocytogenes by macrophages: the search for an immunogenic molecule in antigen presentation. J Immunol. 1984 Jan;132(1):323–331. [PubMed] [Google Scholar]
  3. Allen P. M., Unanue E. R. Differential requirements for antigen processing by macrophages for lysozyme-specific T cell hybridomas. J Immunol. 1984 Mar;132(3):1077–1079. [PubMed] [Google Scholar]
  4. Babbitt B. P., Matsueda G., Haber E., Unanue E. R., Allen P. M. Antigenic competition at the level of peptide-Ia binding. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4509–4513. doi: 10.1073/pnas.83.12.4509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bjorkman P. J., Saper M. A., Samraoui B., Bennett W. S., Strominger J. L., Wiley D. C. Structure of the human class I histocompatibility antigen, HLA-A2. Nature. 1987 Oct 8;329(6139):506–512. doi: 10.1038/329506a0. [DOI] [PubMed] [Google Scholar]
  6. Bogen B., Malissen B., Haas W. Idiotope-specific T cell clones that recognize syngeneic immunoglobulin fragments in the context of class II molecules. Eur J Immunol. 1986 Nov;16(11):1373–1378. doi: 10.1002/eji.1830161110. [DOI] [PubMed] [Google Scholar]
  7. Clayberger C., Parham P., Rothbard J., Ludwig D. S., Schoolnik G. K., Krensky A. M. HLA-A2 peptides can regulate cytolysis by human allogeneic T lymphocytes. Nature. 1987 Dec 24;330(6150):763–765. doi: 10.1038/330763a0. [DOI] [PubMed] [Google Scholar]
  8. Dos Reis G. A., Shevach E. M. Antigen-presenting cells from nonresponder strain 2 guinea pigs are fully competent to present bovine insulin B chain to responder strain 13 T cells. Evidence against a determinant selection model and in favor of a clonal deletion model of immune response gene function. J Exp Med. 1983 Apr 1;157(4):1287–1299. doi: 10.1084/jem.157.4.1287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gilman J. G. Mouse haemoglobin beta chains. Comparative sequence data on adult major and minor beta chains from two species, Mus musculus and Mus cervicolor. Biochem J. 1976 Oct 1;159(1):43–53. doi: 10.1042/bj1590043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Groves E. S., Singer A. Role of the H-2 complex in the induction of T cell tolerance to self minor histocompatibility antigens. J Exp Med. 1983 Nov 1;158(5):1483–1497. doi: 10.1084/jem.158.5.1483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lakey E. K., Margoliash E., Flouret G., Pierce S. K. Peptides related to the antigenic determinant block T cell recognition of the native protein as processed by antigen-presenting cells. Eur J Immunol. 1986 Jul;16(7):721–727. doi: 10.1002/eji.1830160702. [DOI] [PubMed] [Google Scholar]
  12. Matzinger P., Zamoyska R., Waldmann H. Self tolerance is H-2-restricted. Nature. 1984 Apr 19;308(5961):738–741. doi: 10.1038/308738a0. [DOI] [PubMed] [Google Scholar]
  13. Nossal G. J. Cellular mechanisms of immunologic tolerance. Annu Rev Immunol. 1983;1:33–62. doi: 10.1146/annurev.iy.01.040183.000341. [DOI] [PubMed] [Google Scholar]
  14. Oi V. T., Jones P. P., Goding J. W., Herzenberg L. A., Herzenberg L. A. Properties of monoclonal antibodies to mouse Ig allotypes, H-2, and Ia antigens. Curr Top Microbiol Immunol. 1978;81:115–120. doi: 10.1007/978-3-642-67448-8_18. [DOI] [PubMed] [Google Scholar]
  15. Ozato K., Mayer N., Sachs D. H. Hybridoma cell lines secreting monoclonal antibodies to mouse H-2 and Ia antigens. J Immunol. 1980 Feb;124(2):533–540. [PubMed] [Google Scholar]
  16. Raff M. C. Do antigen-presenting cells distinguish self from non-self? Nature. 1982 Aug 26;298(5877):791–792. doi: 10.1038/298791a0. [DOI] [PubMed] [Google Scholar]
  17. Rammensee H. G., Bevan M. J. Evidence from in vitro studies that tolerance to self antigens is MHC-restricted. Nature. 1984 Apr 19;308(5961):741–744. doi: 10.1038/308741a0. [DOI] [PubMed] [Google Scholar]
  18. Rock K. L., Benacerraf B., Abbas A. K. Antigen presentation by hapten-specific B lymphocytes. I. Role of surface immunoglobulin receptors. J Exp Med. 1984 Oct 1;160(4):1102–1113. doi: 10.1084/jem.160.4.1102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Rosenthal A. S. Determinant selection and macrophage function in genetic control of the immune response. Immunol Rev. 1978;40:136–152. doi: 10.1111/j.1600-065x.1978.tb00404.x. [DOI] [PubMed] [Google Scholar]
  20. Rosenthal A. S., Shevach E. M. Function of macrophages in antigen recognition by guinea pig T lymphocytes. I. Requirement for histocompatible macrophages and lymphocytes. J Exp Med. 1973 Nov 1;138(5):1194–1212. doi: 10.1084/jem.138.5.1194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Russell E. S., McFarland E. C. Genetics of mouse hemoglobins. Ann N Y Acad Sci. 1974 Nov 29;241(0):25–38. doi: 10.1111/j.1749-6632.1974.tb21864.x. [DOI] [PubMed] [Google Scholar]
  22. Shimonkevitz R., Kappler J., Marrack P., Grey H. Antigen recognition by H-2-restricted T cells. I. Cell-free antigen processing. J Exp Med. 1983 Aug 1;158(2):303–316. doi: 10.1084/jem.158.2.303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Unanue E. R. Antigen-presenting function of the macrophage. Annu Rev Immunol. 1984;2:395–428. doi: 10.1146/annurev.iy.02.040184.002143. [DOI] [PubMed] [Google Scholar]
  24. Weinberg D. S., Unanue E. R. Antigen-presenting function of alveolar macrophages: uptake and presentation of Listeria monocytogenes. J Immunol. 1981 Feb;126(2):794–799. [PubMed] [Google Scholar]
  25. Wekerle H., Schwab M., Linington C., Meyermann R. Antigen presentation in the peripheral nervous system: Schwann cells present endogenous myelin autoantigens to lymphocytes. Eur J Immunol. 1986 Dec;16(12):1551–1557. doi: 10.1002/eji.1830161214. [DOI] [PubMed] [Google Scholar]
  26. Whitney J. B., 3rd, Cobb R. R., Popp R. A., O'Rourke T. W. Detection of neutral amino acid substitutions in proteins. Proc Natl Acad Sci U S A. 1985 Nov;82(22):7646–7650. doi: 10.1073/pnas.82.22.7646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Winchester G., Sunshine G. H., Nardi N., Mitchison N. A. Antigen-presenting cells do not discriminate between self and nonself. Immunogenetics. 1984;19(6):487–491. doi: 10.1007/BF00403439. [DOI] [PubMed] [Google Scholar]
  28. Ziegler H. K., Unanue E. R. Decrease in macrophage antigen catabolism caused by ammonia and chloroquine is associated with inhibition of antigen presentation to T cells. Proc Natl Acad Sci U S A. 1982 Jan;79(1):175–178. doi: 10.1073/pnas.79.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Zinkernagel R. M., Doherty P. C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974 Apr 19;248(5450):701–702. doi: 10.1038/248701a0. [DOI] [PubMed] [Google Scholar]

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