Skip to main content
NCBI home page
Immunology logoLink to Immunology
. 1997 Oct;92(2):206–213. doi: 10.1046/j.1365-2567.1997.00347.x

Apoptosis with FasL+ cell infiltration in the periphery and thymus of corrected autoimmune mice.

T Kobata 1, K Takasaki 1, H Asahara 1, N M Hong 1, K Masuko-Hongo 1, T Kato 1, S Hirose 1, T Shirai 1, N Kayagaki 1, H Yagita 1, K Okumura 1, K Nishioka 1
PMCID: PMC1364060  PMID: 9415028

Abstract

Fas (CD95) ligand (L) is a death factor that binds to its receptor, Fas, and induces apoptotic cell death, a crucial process in immunological tolerance. gld (generalized lymphoproliferative disorder) mice, which have a point mutation in the FasL gene, develop spontaneous systemic autoimmune syndromes characterized by hypergammaglobulinaemia and lymphoid hyperplasia owing to accumulation of abnormal B220+ CD3+ cells. Transplantation of wild-type (wt) bone marrow cells into old gld mice on the same strain background results in normalization of autoimmune syndromes. We characterized the cellular mechanisms (functionally and histologically) of the above phenomena in gld mice after bone marrow transplantation (BMT) to determine the role of apoptosis via Fas/FasL interactions in inducing and maintaining self-tolerance in vivo. Activated splenocytes from wt and BMT (wt to gld) mice showed significant cytotoxic activity against Fas transfectant cells while those from BMT (gld to gld) mice did not. Cells in the thymus, spleen and lymph nodes of gld mice uniformly upregulated Fas expression and were sensitive to Fas-mediated apoptosis compared with those in wt mice. Cells sensitive to Fas-mediated apoptosis in gld mice resided not only among abnormal B220+ CD3+ cells but also among conventional lymphocytes. More importantly, histological analysis revealed that cells in the spleen, lymph nodes and thymus frequently underwent apoptosis with infiltration of FasL+ cells in BMT (wt to gld) mice compared with BMT (gld to gld) mice. Our results indicated that apoptosis via Fas/FasL interactions can directly eliminate pathogenic cells responsible for autoimmunity in the periphery and possibly in the thymus in vivo.

Full text

PDF
206

Images in this article

211Figure 4
on p.211

Selected References

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

  1. Allen R. D., Marshall J. D., Roths J. B., Sidman C. L. Differences defined by bone marrow transplantation suggest that lpr and gld are mutations of genes encoding an interacting pair of molecules. J Exp Med. 1990 Nov 1;172(5):1367–1375. doi: 10.1084/jem.172.5.1367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arase H., Arase N., Kobayashi Y., Nishimura Y., Yonehara S., Onoé K. Cytotoxicity of fresh NK1.1+ T cell receptor alpha/beta+ thymocytes against a CD4+8+ thymocyte population associated with intact Fas antigen expression on the target. J Exp Med. 1994 Aug 1;180(2):423–432. doi: 10.1084/jem.180.2.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arase H., Arase N., Saito T. Fas-mediated cytotoxicity by freshly isolated natural killer cells. J Exp Med. 1995 Mar 1;181(3):1235–1238. doi: 10.1084/jem.181.3.1235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chu J. L., Ramos P., Rosendorff A., Nikolić-Zugić J., Lacy E., Matsuzawa A., Elkon K. B. Massive upregulation of the Fas ligand in lpr and gld mice: implications for Fas regulation and the graft-versus-host disease-like wasting syndrome. J Exp Med. 1995 Jan 1;181(1):393–398. doi: 10.1084/jem.181.1.393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cohen P. L., Eisenberg R. A. Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. Annu Rev Immunol. 1991;9:243–269. doi: 10.1146/annurev.iy.09.040191.001331. [DOI] [PubMed] [Google Scholar]
  6. Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Giese T., Davidson W. F. Chronic treatment of C3H-lpr/lpr and C3H-gld/gld mice with anti-CD8 monoclonal antibody prevents the accumulation of double negative T cells but not autoantibody production. J Immunol. 1994 Feb 15;152(4):2000–2010. [PubMed] [Google Scholar]
  8. Jacobson B. A., Panka D. J., Nguyen K. A., Erikson J., Abbas A. K., Marshak-Rothstein A. Anatomy of autoantibody production: dominant localization of antibody-producing cells to T cell zones in Fas-deficient mice. Immunity. 1995 Oct;3(4):509–519. doi: 10.1016/1074-7613(95)90179-5. [DOI] [PubMed] [Google Scholar]
  9. Kayagaki N., Kawasaki A., Ebata T., Ohmoto H., Ikeda S., Inoue S., Yoshino K., Okumura K., Yagita H. Metalloproteinase-mediated release of human Fas ligand. J Exp Med. 1995 Dec 1;182(6):1777–1783. doi: 10.1084/jem.182.6.1777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kayagaki N., Yamaguchi N., Nagao F., Matsuo S., Maeda H., Okumura K., Yagita H. Polymorphism of murine Fas ligand that affects the biological activity. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3914–3919. doi: 10.1073/pnas.94.8.3914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lynch D. H., Ramsdell F., Alderson M. R. Fas and FasL in the homeostatic regulation of immune responses. Immunol Today. 1995 Dec;16(12):569–574. doi: 10.1016/0167-5699(95)80079-4. [DOI] [PubMed] [Google Scholar]
  12. Lynch D. H., Watson M. L., Alderson M. R., Baum P. R., Miller R. E., Tough T., Gibson M., Davis-Smith T., Smith C. A., Hunter K. The mouse Fas-ligand gene is mutated in gld mice and is part of a TNF family gene cluster. Immunity. 1994 May;1(2):131–136. doi: 10.1016/1074-7613(94)90106-6. [DOI] [PubMed] [Google Scholar]
  13. MacDonald G. C., Kakkanaiah V. N., Sobel E. S., Cohen P. L., Eisenberg R. A. In vivo depletion of Thy-1-positive cells originating from normal bone marrow abrogates the suppression of gld disease in normal-gld mixed bone marrow chimeras. J Immunol. 1995 Jan 1;154(1):444–449. [PubMed] [Google Scholar]
  14. Mountz J. D., Smith T. M., Toth K. S. Altered expression of self-reactive T cell receptor V beta regions in autoimmune mice. J Immunol. 1990 Mar 15;144(6):2159–2166. [PubMed] [Google Scholar]
  15. Nagata S., Suda T. Fas and Fas ligand: lpr and gld mutations. Immunol Today. 1995 Jan;16(1):39–43. doi: 10.1016/0167-5699(95)80069-7. [DOI] [PubMed] [Google Scholar]
  16. Nishimura Y., Ishii A., Kobayashi Y., Yamasaki Y., Yonehara S. Expression and function of mouse Fas antigen on immature and mature T cells. J Immunol. 1995 May 1;154(9):4395–4403. [PubMed] [Google Scholar]
  17. Ogasawara J., Suda T., Nagata S. Selective apoptosis of CD4+CD8+ thymocytes by the anti-Fas antibody. J Exp Med. 1995 Feb 1;181(2):485–491. doi: 10.1084/jem.181.2.485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Rathmell J. C., Cooke M. P., Ho W. Y., Grein J., Townsend S. E., Davis M. M., Goodnow C. C. CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD4+ T cells. Nature. 1995 Jul 13;376(6536):181–184. doi: 10.1038/376181a0. [DOI] [PubMed] [Google Scholar]
  19. Seino K., Kayagaki N., Bashuda H., Okumura K., Yagita H. Contribution of Fas ligand to cardiac allograft rejection. Int Immunol. 1996 Sep;8(9):1347–1354. doi: 10.1093/intimm/8.9.1347. [DOI] [PubMed] [Google Scholar]
  20. Sidman C. L., Marshall J. D., Von Boehmer H. Transgenic T cell receptor interactions in the lymphoproliferative and autoimmune syndromes of lpr and gld mutant mice. Eur J Immunol. 1992 Feb;22(2):499–504. doi: 10.1002/eji.1830220231. [DOI] [PubMed] [Google Scholar]
  21. Singer G. G., Abbas A. K. The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity. 1994 Aug;1(5):365–371. doi: 10.1016/1074-7613(94)90067-1. [DOI] [PubMed] [Google Scholar]
  22. Sobel E. S., Kakkanaiah V. N., Kakkanaiah M., Cohen P. L., Eisenberg R. A. Co-infusion of normal bone marrow partially corrects the gld T-cell defect. Evidence for an intrinsic and extrinsic role for Fas ligand. J Immunol. 1995 Jan 1;154(1):459–464. [PubMed] [Google Scholar]
  23. Suda T., Takahashi T., Golstein P., Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell. 1993 Dec 17;75(6):1169–1178. doi: 10.1016/0092-8674(93)90326-l. [DOI] [PubMed] [Google Scholar]
  24. Takahashi T., Tanaka M., Brannan C. I., Jenkins N. A., Copeland N. G., Suda T., Nagata S. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell. 1994 Mar 25;76(6):969–976. doi: 10.1016/0092-8674(94)90375-1. [DOI] [PubMed] [Google Scholar]
  25. Watanabe-Fukunaga R., Brannan C. I., Copeland N. G., Jenkins N. A., Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992 Mar 26;356(6367):314–317. doi: 10.1038/356314a0. [DOI] [PubMed] [Google Scholar]
  26. Weih F., Ryseck R. P., Chen L., Bravo R. Apoptosis of nur77/N10-transgenic thymocytes involves the Fas/Fas ligand pathway. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5533–5538. doi: 10.1073/pnas.93.11.5533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wu J., Wilson J., He J., Xiang L., Schur P. H., Mountz J. D. Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J Clin Invest. 1996 Sep 1;98(5):1107–1113. doi: 10.1172/JCI118892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Zhou T., Bluethmann H., Eldridge J., Berry K., Mountz J. D. Origin of CD4-CD8-B220+ T cells in MRL-lpr/lpr mice. Clues from a T cell receptor beta transgenic mouse. J Immunol. 1993 Apr 15;150(8 Pt 1):3651–3667. [PubMed] [Google Scholar]

Articles from Immunology are provided here courtesy of British Society for Immunology

RESOURCES