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. 1995 Aug;96(2):727–732. doi: 10.1172/JCI118116

FK506 augments activation-induced programmed cell death of T lymphocytes in vivo.

K Migita 1, K Eguchi 1, Y Kawabe 1, T Tsukada 1, A Mizokami 1, S Nagataki 1
PMCID: PMC185256  PMID: 7543492

Abstract

FK506 is an immunosuppressive drug that inhibits T cell receptor-mediated signal transduction. This drug can induce immunological tolerance in allograft recipients. In this study, we investigated the in vivo effects of FK506 on T cell receptor-mediated apoptosis induction. Injection of anti-CD3 antibody (Ab) in mice resulted in the elimination of CD4+ CD8+ thymocytes by DNA fragmentation. FK506 treatment significantly augmented thymic apoptosis induced by in vivo anti-CD3 Ab administration. Increased thymic apoptosis resulted in the disappearance of CD4+ CD8+ thymocytes after anti-CD3 Ab/FK506 treatment. DNA fragmentation triggered by FK506 was induced exclusively in antigen-stimulated T cells, since enhanced DNA fragmentation induced by in vivo staphylococcal enterotoxin B (SEB) injection was confirmed in SEB-reactive V beta 8+ thymocytes but not in SEB-nonreactive V beta 6+ thymocytes. In addition to thymocytes, mature peripheral T cells also die by activation-induced programmed cell death. A similar effect of FK506 on activation-induced programmed cell death was observed in SEB-activated peripheral spleen T cells. In contrast, cyclosporin A treatment did not enhance activation-induced programmed cell death of thymocytes and peripheral T cells. Apoptosis is required for the generation and maintenance of self-tolerance in the immune system. Our findings suggest that FK506-triggered apoptosis after elimination of antigen-activated T cells may represent a potential mechanism of the immunological tolerance achieved by FK506 treatment.

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Selected References

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  1. Bishop D. K., Li W. Cyclosporin A and FK506 mediate differential effects on T cell activation in vivo. J Immunol. 1992 Feb 15;148(4):1049–1054. [PubMed] [Google Scholar]
  2. Blazar B. R., Taylor P. A., Fitzsimmons W. E., Vallera D. A. FK506 inhibits graft-versus-host disease and bone marrow graft rejection in murine recipients of MHC disparate donor grafts by interfering with mature peripheral T cell expansion post-transplantation. J Immunol. 1994 Aug 15;153(4):1836–1846. [PubMed] [Google Scholar]
  3. Bucy R. P., Xu X. Y., Li J., Huang G. Cyclosporin A-induced autoimmune disease in mice. J Immunol. 1993 Jul 15;151(2):1039–1050. [PubMed] [Google Scholar]
  4. Fowlkes B. J., Schwartz R. H., Pardoll D. M. Deletion of self-reactive thymocytes occurs at a CD4+8+ precursor stage. Nature. 1988 Aug 18;334(6183):620–623. doi: 10.1038/334620a0. [DOI] [PubMed] [Google Scholar]
  5. Janeway C. A., Jr Selective elements for the V beta region of the T cell receptor: Mls and the bacterial toxic mitogens. Adv Immunol. 1991;50:1–53. doi: 10.1016/s0065-2776(08)60821-4. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Kawabe Y., Ochi A. Programmed cell death and extrathymic reduction of Vbeta8+ CD4+ T cells in mice tolerant to Staphylococcus aureus enterotoxin B. Nature. 1991 Jan 17;349(6306):245–248. doi: 10.1038/349245a0. [DOI] [PubMed] [Google Scholar]
  8. Kawabe Y., Ochi A. Selective anergy of V beta 8+,CD4+ T cells in Staphylococcus enterotoxin B-primed mice. J Exp Med. 1990 Oct 1;172(4):1065–1070. doi: 10.1084/jem.172.4.1065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kino T., Hatanaka H., Hashimoto M., Nishiyama M., Goto T., Okuhara M., Kohsaka M., Aoki H., Imanaka H. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo) 1987 Sep;40(9):1249–1255. doi: 10.7164/antibiotics.40.1249. [DOI] [PubMed] [Google Scholar]
  10. Kino T., Hatanaka H., Miyata S., Inamura N., Nishiyama M., Yajima T., Goto T., Okuhara M., Kohsaka M., Aoki H. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 1987 Sep;40(9):1256–1265. doi: 10.7164/antibiotics.40.1256. [DOI] [PubMed] [Google Scholar]
  11. Korngold R., Sprent J. T cell subsets and graft-versus-host disease. Transplantation. 1987 Sep;44(3):335–339. doi: 10.1097/00007890-198709000-00002. [DOI] [PubMed] [Google Scholar]
  12. Laster S. M., Wood J. G., Gooding L. R. Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis. J Immunol. 1988 Oct 15;141(8):2629–2634. [PubMed] [Google Scholar]
  13. Leo O., Foo M., Sachs D. H., Samelson L. E., Bluestone J. A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374–1378. doi: 10.1073/pnas.84.5.1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lin Y. S., Lei H. Y., Low T. L., Shen C. L., Chou L. J., Jan M. S. In vivo induction of apoptosis in immature thymocytes by staphylococcal enterotoxin B. J Immunol. 1992 Aug 15;149(4):1156–1163. [PubMed] [Google Scholar]
  15. MacDonald H. R., Lees R. K. Programmed death of autoreactive thymocytes. Nature. 1990 Feb 15;343(6259):642–644. doi: 10.1038/343642a0. [DOI] [PubMed] [Google Scholar]
  16. Markus P. M., Cai X., Ming W., Demetris A. J., Fung J. J., Starzl T. E. Prevention of graft-versus-host disease following allogeneic bone marrow transplantation in rats using FK506. Transplantation. 1991 Oct;52(4):590–594. doi: 10.1097/00007890-199110000-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. O'Keefe S. J., Tamura J., Kincaid R. L., Tocci M. J., O'Neill E. A. FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature. 1992 Jun 25;357(6380):692–694. doi: 10.1038/357692a0. [DOI] [PubMed] [Google Scholar]
  18. Ochiai T., Nagata M., Nakajima K., Suzuki T., Sakamoto K., Enomoto K., Gunji Y., Uematsu T., Goto T., Hori S. Studies of the effects of FK506 on renal allografting in the beagle dog. Transplantation. 1987 Dec;44(6):729–733. doi: 10.1097/00007890-198712000-00001. [DOI] [PubMed] [Google Scholar]
  19. Perandones C. E., Illera V. A., Peckham D., Stunz L. L., Ashman R. F. Regulation of apoptosis in vitro in mature murine spleen T cells. J Immunol. 1993 Oct 1;151(7):3521–3529. [PubMed] [Google Scholar]
  20. Prud'homme G. J., Parfrey N. A., Vanier L. E. Cyclosporine-induced autoimmunity and immune hyperreactivity. Autoimmunity. 1991;9(4):345–356. doi: 10.3109/08916939108997137. [DOI] [PubMed] [Google Scholar]
  21. Shi Y. F., Bissonnette R. P., Parfrey N., Szalay M., Kubo R. T., Green D. R. In vivo administration of monoclonal antibodies to the CD3 T cell receptor complex induces cell death (apoptosis) in immature thymocytes. J Immunol. 1991 May 15;146(10):3340–3346. [PubMed] [Google Scholar]
  22. Shi Y. F., Sahai B. M., Green D. R. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature. 1989 Jun 22;339(6226):625–626. doi: 10.1038/339625a0. [DOI] [PubMed] [Google Scholar]
  23. Smith C. A., Williams G. T., Kingston R., Jenkinson E. J., Owen J. J. Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature. 1989 Jan 12;337(6203):181–184. doi: 10.1038/337181a0. [DOI] [PubMed] [Google Scholar]
  24. Staerz U. D., Rammensee H. G., Benedetto J. D., Bevan M. J. Characterization of a murine monoclonal antibody specific for an allotypic determinant on T cell antigen receptor. J Immunol. 1985 Jun;134(6):3994–4000. [PubMed] [Google Scholar]
  25. Starzl T. E., Todo S., Fung J., Demetris A. J., Venkataramman R., Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet. 1989 Oct 28;2(8670):1000–1004. doi: 10.1016/s0140-6736(89)91014-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Tocci M. J., Matkovich D. A., Collier K. A., Kwok P., Dumont F., Lin S., Degudicibus S., Siekierka J. J., Chin J., Hutchinson N. I. The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol. 1989 Jul 15;143(2):718–726. [PubMed] [Google Scholar]
  27. Todo S., Ueda Y., Demetris J. A., Imventarza O., Nalesnik M., Venkataramanan R., Makowka L., Starzl T. E. Immunosuppression of canine, monkey, and baboon allografts by FK 506: with special reference to synergism with other drugs and to tolerance induction. Surgery. 1988 Aug;104(2):239–249. [PMC free article] [PubMed] [Google Scholar]
  28. Uckun F. M., Tuel-Ahlgren L., Song C. W., Waddick K., Myers D. E., Kirihara J., Ledbetter J. A., Schieven G. L. Ionizing radiation stimulates unidentified tyrosine-specific protein kinases in human B-lymphocyte precursors, triggering apoptosis and clonogenic cell death. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9005–9009. doi: 10.1073/pnas.89.19.9005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Vanier L. E., Prud'homme G. J. Cyclosporin A markedly enhances superantigen-induced peripheral T cell deletion and inhibits anergy induction. J Exp Med. 1992 Jul 1;176(1):37–46. doi: 10.1084/jem.176.1.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Webb S., Morris C., Sprent J. Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity. Cell. 1990 Dec 21;63(6):1249–1256. doi: 10.1016/0092-8674(90)90420-j. [DOI] [PubMed] [Google Scholar]
  31. Weller M., Constam D. B., Malipiero U., Fontana A. Transforming growth factor-beta 2 induces apoptosis of murine T cell clones without down-regulating bcl-2 mRNA expression. Eur J Immunol. 1994 Jun;24(6):1293–1300. doi: 10.1002/eji.1830240608. [DOI] [PubMed] [Google Scholar]
  32. Wyllie A. H., Kerr J. F., Currie A. R. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. doi: 10.1016/s0074-7696(08)62312-8. [DOI] [PubMed] [Google Scholar]
  33. Yoshimura N., Matsui S., Hamashima T., Oka T. Effect of a new immunosuppressive agent, FK506, on human lymphocyte responses in vitro. I. Inhibition of expression of alloantigen-activated suppressor cells, as well as induction of alloreactivity. Transplantation. 1989 Feb;47(2):351–356. doi: 10.1097/00007890-198902000-00034. [DOI] [PubMed] [Google Scholar]

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