Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1989 Jul 1;170(1):87–104. doi: 10.1084/jem.170.1.87

Tolerance in transgenic mice expressing class II major histocompatibility complex on pancreatic acinar cells

PMCID: PMC2189391  PMID: 2526197

Abstract

To study the nature of tolerance to antigens not expressed by cells of the lymphoid system, expression of class II MHC I-E was targeted to the acinar cells of the exocrine pancreas in transgenic mice (elastase [EL]- I-E). Despite the absence of detectable I-E in the thymus of EL-I-E transgenic mice, both thymocytes and peripheral T lymphocytes were tolerant to I-E, and the pancreas was free of autoimmune infiltrates. Nontolerant T cells adoptively transferred into irradiated or T- depleted transgenic mice rapidly destroy the I-E+ components of the pancreas; however, adoptive transfer of nontolerant T lymphocytes into nonirradiated transgenic mice do not. These results suggest that tolerance in transgenic mice is maintained by some peripheral tolerance mechanism. However, further studies indicate that tolerance in transgenic mice is not maintained by specific Ts cells. For example, cell mixing experiments both in vitro and in vivo fail to reveal dominant unresponsiveness. Furthermore, nontolerant T cells injected into otherwise unmanipulated EL-I-E mice can be primed in situ (by injections of I-E+ spleen cells) to destroy the I-E+ acinar cells.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

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

  1. Adams T. E., Alpert S., Hanahan D. Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic beta cells. Nature. 1987 Jan 15;325(6101):223–228. doi: 10.1038/325223a0. [DOI] [PubMed] [Google Scholar]
  2. Allison J., Campbell I. L., Morahan G., Mandel T. E., Harrison L. C., Miller J. F. Diabetes in transgenic mice resulting from over-expression of class I histocompatibility molecules in pancreatic beta cells. Nature. 1988 Jun 9;333(6173):529–533. doi: 10.1038/333529a0. [DOI] [PubMed] [Google Scholar]
  3. Bandeira A., Coutinho A., Carnaud C., Jacquemart F., Forni L. Transplantation tolerance correlates with high levels of T- and B-lymphocyte activity. Proc Natl Acad Sci U S A. 1989 Jan;86(1):272–276. doi: 10.1073/pnas.86.1.272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bellgrau D., Wilson D. B. Immunological studies of T-cell receptors. I. Specifically induced resistance to graft-versus-host disease in rats mediated by host T-cell immunity to alloreactive parental T cells. J Exp Med. 1978 Jul 1;148(1):103–114. doi: 10.1084/jem.148.1.103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brinster R. L., Chen H. Y., Trumbauer M. E., Yagle M. K., Palmiter R. D. Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4438–4442. doi: 10.1073/pnas.82.13.4438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brinster R. L., Palmiter R. D. Introduction of genes into the germ line of animals. Harvey Lect. 1984 1985;80:1–38. [PMC free article] [PubMed] [Google Scholar]
  7. Burkly L. C., Lo D., Cowing C., Palmiter R. D., Brinster R. L., Flavell R. A. Selective expression of class II E alpha d gene in transgenic mice. J Immunol. 1989 Mar 15;142(6):2081–2088. [PubMed] [Google Scholar]
  8. Fink P. J., Bevan M. J., Weissman I. L. Thymic cytotoxic T lymphocytes are primed in vivo to minor histocompatibility antigens. J Exp Med. 1984 Feb 1;159(2):436–451. doi: 10.1084/jem.159.2.436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gaspari A. A., Jenkins M. K., Katz S. I. Class II MHC-bearing keratinocytes induce antigen-specific unresponsiveness in hapten-specific Th1 clones. J Immunol. 1988 Oct 1;141(7):2216–2220. [PubMed] [Google Scholar]
  10. Hammer R. E., Swift G. H., Ornitz D. M., Quaife C. J., Palmiter R. D., Brinster R. L., MacDonald R. J. The rat elastase I regulatory element is an enhancer that directs correct cell specificity and developmental onset of expression in transgenic mice. Mol Cell Biol. 1987 Aug;7(8):2956–2967. doi: 10.1128/mcb.7.8.2956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jackson R., Rassi N., Crump T., Haynes B., Eisenbarth G. S. The BB diabetic rat. Profound T-cell lymphocytopenia. Diabetes. 1981 Oct;30(10):887–889. doi: 10.2337/diab.30.10.887. [DOI] [PubMed] [Google Scholar]
  12. Jenkins M. K., Ashwell J. D., Schwartz R. H. Allogeneic non-T spleen cells restore the responsiveness of normal T cell clones stimulated with antigen and chemically modified antigen-presenting cells. J Immunol. 1988 May 15;140(10):3324–3330. [PubMed] [Google Scholar]
  13. Jenkins M. K., Schwartz R. H. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med. 1987 Feb 1;165(2):302–319. doi: 10.1084/jem.165.2.302. [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. Kelly C. J., Silvers W. K., Neilson E. G. Tolerance to parenchymal self. Regulatory role of major histocompatibility complex-restricted, OX8+ suppressor T cells specific for autologous renal tubular antigen in experimental interstitial nephritis. J Exp Med. 1985 Dec 1;162(6):1892–1903. doi: 10.1084/jem.162.6.1892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kimura H., Pickard A., Wilson D. B. Analysis of T cell populations that induce and mediate specific resistance to graft-versus-host disease in rats. J Exp Med. 1984 Sep 1;160(3):652–658. doi: 10.1084/jem.160.3.652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kojima A., Prehn R. T. Genetic susceptibility to post-thymectomy autoimmune diseases in mice. Immunogenetics. 1981;14(1-2):15–27. doi: 10.1007/BF00344296. [DOI] [PubMed] [Google Scholar]
  18. Lamb J. R., Skidmore B. J., Green N., Chiller J. M., Feldmann M. Induction of tolerance in influenza virus-immune T lymphocyte clones with synthetic peptides of influenza hemagglutinin. J Exp Med. 1983 May 1;157(5):1434–1447. doi: 10.1084/jem.157.5.1434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lo D., Burkly L. C., Widera G., Cowing C., Flavell R. A., Palmiter R. D., Brinster R. L. Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cells. Cell. 1988 Apr 8;53(1):159–168. doi: 10.1016/0092-8674(88)90497-7. [DOI] [PubMed] [Google Scholar]
  20. Marrack P., Kappler J. T cells can distinguish between allogeneic major histocompatibility complex products on different cell types. Nature. 1988 Apr 28;332(6167):840–843. doi: 10.1038/332840a0. [DOI] [PubMed] [Google Scholar]
  21. Marrack P., Lo D., Brinster R., Palmiter R., Burkly L., Flavell R. H., Kappler J. The effect of thymus environment on T cell development and tolerance. Cell. 1988 May 20;53(4):627–634. doi: 10.1016/0092-8674(88)90578-8. [DOI] [PubMed] [Google Scholar]
  22. Michie S. A., Kirkpatrick E. A., Rouse R. V. Rare peripheral T cells migrate to and persist in normal mouse thymus. J Exp Med. 1988 Nov 1;168(5):1929–1934. doi: 10.1084/jem.168.5.1929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Naparstek Y., Holoshitz J., Eisenstein S., Reshef T., Rappaport S., Chemke J., Ben-Nun A., Cohen I. R. Effector T lymphocyte line cells migrate to the thymus and persist there. Nature. 1982 Nov 18;300(5889):262–264. doi: 10.1038/300262a0. [DOI] [PubMed] [Google Scholar]
  24. Palmiter R. D., Brinster R. L. Germ-line transformation of mice. Annu Rev Genet. 1986;20:465–499. doi: 10.1146/annurev.ge.20.120186.002341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Parham P. Intolerable secretion in tolerant transgenic mice. Nature. 1988 Jun 9;333(6173):500–503. doi: 10.1038/333500a0. [DOI] [PubMed] [Google Scholar]
  26. Quill H., Schwartz R. H. Stimulation of normal inducer T cell clones with antigen presented by purified Ia molecules in planar lipid membranes: specific induction of a long-lived state of proliferative nonresponsiveness. J Immunol. 1987 Jun 1;138(11):3704–3712. [PubMed] [Google Scholar]
  27. Sakaguchi S., Takahashi T., Nishizuka Y. Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis. J Exp Med. 1982 Dec 1;156(6):1577–1586. doi: 10.1084/jem.156.6.1577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sarvetnick N., Liggitt D., Pitts S. L., Hansen S. E., Stewart T. A. Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell. 1988 Mar 11;52(5):773–782. doi: 10.1016/0092-8674(88)90414-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Scollay R., Wilson A., D'Amico A., Kelly K., Egerton M., Pearse M., Wu L., Shortman K. Developmental status and reconstitution potential of subpopulations of murine thymocytes. Immunol Rev. 1988 Aug;104:81–120. doi: 10.1111/j.1600-065x.1988.tb00760.x. [DOI] [PubMed] [Google Scholar]
  30. Sprent J., Lo D., Gao E. K., Ron Y. T cell selection in the thymus. Immunol Rev. 1988 Jan;101:173–190. doi: 10.1111/j.1600-065x.1988.tb00737.x. [DOI] [PubMed] [Google Scholar]
  31. Sprent J., Schaefer M., Lo D., Korngold R. Properties of purified T cell subsets. II. In vivo responses to class I vs. class II H-2 differences. J Exp Med. 1986 Apr 1;163(4):998–1011. doi: 10.1084/jem.163.4.998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Taguchi O., Nishizuka Y. Self tolerance and localized autoimmunity. Mouse models of autoimmune disease that suggest tissue-specific suppressor T cells are involved in self tolerance. J Exp Med. 1987 Jan 1;165(1):146–156. doi: 10.1084/jem.165.1.146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Widera G., Burkly L. C., Pinkert C. A., Böttger E. C., Cowing C., Palmiter R. D., Brinster R. L., Flavell R. A. Transgenic mice selectively lacking MHC class II (I-E) antigen expression on B cells: an in vivo approach to investigate Ia gene function. Cell. 1987 Oct 23;51(2):175–187. doi: 10.1016/0092-8674(87)90145-0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES