Clonal Anergy in Transgenic Mice with Pancreatic Expression of MHC Class II I-E

  • L. C. Burkly
  • D. Lo
  • O. Kanagawa
  • R. L. Brinster
  • R. A. Flavell
Conference paper


Experimental conditions whereby T cell tolerance can be established and maintained have been investigated and defined in many systems. However, the mechanisms of tolerance in these systems and their relevance to tolerance induction during normal T cell development in vivo is still not fully understood. The development of monoclonal antibodies (mAbs) to T cell receptor (TcR) vβ chains, and the observation that certain Vβ chains are associated with reactivity to antigens such as I-E (Kappler, et al. 1987b) and Mls (Kappler, et al. 1988; MacDonald, et al. 1988) has provided in vivo evidence for clonal deletion. Thus, Kappler et al. showed that T cells utilizing the Vβl7a TcR gene which is identified by mAb KJ23 are generally reactive to I-E and are present in I-E negative mice but deleted in the thymus of I-E expressing mouse strains (Kappler, et al. 1987ab, Marrack, et al. 1988). The ability to monitor the presence or absence of antigen-reactive T cells offers a valuable alternative to functional measurements and provides a means to determine mechanisms of T cell tolerance. There is now in vitro evidence for clonal paralysis of T cells. T cell clones are reportedly inactivated upon exposure to antigen in the presence of human T cell clones (Lamb, et al. 1983), chemically modified spleen cells (Jenkins and Schwartz, 1987), purified MHC class II on planar membranes (Quill and Schwartz, 1987), class II+ keratinocytes (Gaspari, et al. 1988), and I-E+ islet cells (Markmann, et al. 1988).


Stimulation Index Cell Tolerance Clonal Deletion Howard Hughes Medical Institute Clonal Anergy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bill, J, Appel, VB, Palmer, E (1988) An analysis of T-cell receptor variable region gene expression in major histocompatibility complex disparate mice. Proc Natl Sci USA 85: 9184CrossRefGoogle Scholar
  2. Bill, J, Kanagawa, O, Woodland, DL, Palmer, E (1989) The MHC molecule I-E is necessary but not sufficient for the clonal deletion of vβll- bearing T cells. J Exp Med 169: 1405PubMedCrossRefGoogle Scholar
  3. Bruce, J, Symington, FW, McKearn, TJ, Sprent, JJ (1981) A monoclonal antibody discriminating between subsets of T and B cells. J Immun 127: 2496PubMedGoogle Scholar
  4. Burkly, LC, Lo, D, Brinster, RL, Flavell, RA (1989) I-E transgenic mice: A model system to dissect the regulation and function of MHC class II genes in vivo. Immunologic Research (in press)Google Scholar
  5. Crispe, IN, Bevan, MJ, Staerz, U (1985) Selective activation of Lyt 2+ precursor T cells by ligation of the antigen receptor. Nature 317: 627PubMedCrossRefGoogle Scholar
  6. Frelinger, J, Sing, A, Infante, A, Fathman, CG (1984) Clonotypic antibodies which stimulate T cell clone proliferation. Immunol Rev 81: 21PubMedCrossRefGoogle Scholar
  7. Gaspari, AA, Jenkins, MK, Katz, SI (1988) Class II MHC-bearing keratinocytes induce antigen-specific unresponsiveness in hapten-specific TH1 clones. J Immunol 141: 2216PubMedGoogle Scholar
  8. Jenkins, MK, Schwartz, RH (1987) Antigen presentation by chemically modified splenocytes induced antigen-specific T cell unresponsiveness The MHC molecule I-E is necessary but not sufficient for the clonal deletion of vβll- bearing T cellsin vitro and in vivo. J Exp Med 165: 302PubMedCrossRefGoogle Scholar
  9. Kappler, JW, Roehm, N, Marrack, P (1987) T cell tolerance by clonal elimination in the thymus. Cell 49: 273PubMedCrossRefGoogle Scholar
  10. Kappler, JW, Staerz, U, White, J, Marrack, P (1988) Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex. Nature 332: 35PubMedCrossRefGoogle Scholar
  11. Kappler, JW, Wade, T, White, J, Kushnir, E, Blackman, M, Bill, J, Roehm, N, Marrack, P (1987) A T cell receptor Vβ segment that imparts reactivity to a class II major histocompatibility complex product. Cell 49: 263–271PubMedCrossRefGoogle Scholar
  12. Kaye, JA, Porcelli, S, Tite, J, Jones, B, Janeway, CAJr (1983) Both a monoclonal antibody and antisera specific for determinants unique to individual cloned helper T cell lines can substitute for antigen and antigen-presenting cells in the activation of T cells. J Exp Med 158: 836PubMedCrossRefGoogle Scholar
  13. Lamb, JR, Skidmore, BJ, Green, N, Chiller, JM, Feldmann, MJ (1983) Induction of tolerance in influenza virus-immune T lymphocyte clones with synthetic peptides of influenza hemagglutinin. J Exp Med 157: 1434PubMedCrossRefGoogle Scholar
  14. Leo, O, Foo, M, Sachs, DH, Samelson, LE, Bluestone, JA (1987) Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci USA 84: 1374PubMedCrossRefGoogle Scholar
  15. Lo, D, Burkly, LC, Flavell, RA, Palmiter, RD, Brinster (1989) Tolerance in transgenic mice expressing class II MHC on pancreatic acinar cells. J Exp Med (in press)Google Scholar
  16. Lo, D, Burkly, LC, Widera, G, Cowing, C, Flavell, RA, Palmiter, RD, Brinster, RL (1988) Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cells. Cell 53: 159PubMedCrossRefGoogle Scholar
  17. MacDonald, HR, Schneider, R, Lees, RK, Howe, RC, Acha-Orbea, H, Festenstein, H, Zinkernagel, RM, Hentgartner, H (1988) T cell receptor use predicts reactivity and tolerance to MLsa-encoded antigens. Nature 332: 40PubMedCrossRefGoogle Scholar
  18. Madsen, JC, Superina, RA, Wood, KJ, Morris, PJ (1988) Immunological unresponsiveness induced by recipient cells transfected with donor MHC genes. Nature 332: 161PubMedCrossRefGoogle Scholar
  19. Manger, B, Weiss, A, Weyand, C, Goronzy, J, Stobo, JD (1985) T cell activation: Differences in the signals required for IL-2 production by nonactivated and activated T cells. J Immunol 135: 3669PubMedGoogle Scholar
  20. Markmann, J, Lo, D, Naji, A, Palmiter, RD, Brinster, RL, Heber-Katz, E (1988) Antigen presenting function of class II MHC expressing pancreatic beta cells. Nature 336: 476PubMedCrossRefGoogle Scholar
  21. Marrack, P, Kappler, J (1988) T cells can distinguish between allogeneic major histocompatibility complex products on different cell types. Nature 332: 840PubMedCrossRefGoogle Scholar
  22. Marrack, P, Lo, D, Brinster, R, Palmiter, R, Burkly, L, Flavell, RA, Kappler, JW (1988) The effect of thymus environment on T cell development and tolerance. Cell 53: 627PubMedCrossRefGoogle Scholar
  23. Matzinger, P, Bevan MJ (1977) Hypothesis: Why do so many lymphocytes respond to major histocompatibility antigens? Cell Immun 29: 1CrossRefGoogle Scholar
  24. Morahan, G, Allison, J, Miller, JFAP (1989) Tolerance of class I histocompatibility antigens expresses extrathymically. Nature 339: 622PubMedCrossRefGoogle Scholar
  25. Murphy, DB, Lo, D, Rath, S, Brinster, RL, Flavell, RA, Slanetz, A, Janeway, CAJr (1989) A novel MHC class II epitope expressed in thymic medulla but not cortex. Nature 338: 7 65Google Scholar
  26. Quill, H, Schwartz, RH (1987) Stimulation of normal inducer T cell clones with antigen presented by purified la molecules in planar lipid membranes: specific induction of a long-lived state of proliferative nonresponsiveness. J Immunol 138: 3704PubMedGoogle Scholar
  27. Rammensee, H-G, Kroschewski, R, Frangoulis, B (1989) Clonal anergy induced in mature Vβ6+ T lymphocytes on immunizing Mls-1b mice with Mls-1a expressing cells. Nature 339: 541PubMedCrossRefGoogle Scholar
  28. Widera, G, Burkly, LC, Pinkert, CA, Boettger, E, Cowing, C, Palmiter, RD, Brinster, RL, Flavell, RA (1987) Transgenic mice selectively lacking MHC class II (I-E)antigen expression on B cells: An in vivo approach to investigate la gene function. Cell 51: 175PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • L. C. Burkly
    • 1
  • D. Lo
    • 2
  • O. Kanagawa
    • 3
  • R. L. Brinster
    • 2
  • R. A. Flavell
    • 1
    • 4
  1. 1.Biogen., Inc.CambridgeUSA
  2. 2.Laboratory of Reproductive Physiology, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Lilly Research LaboratoryLa JollaUSA
  4. 4.Howard Hughes Medical Institute, Section of ImmunobiologyYale University School of MedicineNew HavenUSA

Personalised recommendations