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. 1996 Apr 2;133(2):335–343. doi: 10.1083/jcb.133.2.335

Fas and Fas ligand in embryos and adult mice: ligand expression in several immune-privileged tissues and coexpression in adult tissues characterized by apoptotic cell turnover

PMCID: PMC2120795  PMID: 8609166

Abstract

The cell surface receptor Fas (FasR, Apo-1, CD95) and its ligand (FasL) are mediators of apoptosis that have been shown to be implicated in the peripheral deletion of autoimmune cells, activation-induced T cell death, and one of the two major cytolytic pathways mediated by CD8+ cytolytic T cells. To gain further understanding of the Fas system., we have analyzed Fas and FasL expression during mouse development and in adult tissues. In developing mouse embryos, from 16.5 d onwards, Fas mRNA is detectable in distinct cell types of the developing sinus, thymus, lung, and liver, whereas FasL expression is restricted to submaxillary gland epithelial cells and the developing nervous system. Significant Fas and FasL expression were observed in several nonlymphoid cell types during embryogenesis, and generally Fas and FasL expression were not localized to characteristic sites of programmed cell death. In the adult mouse, RNase protection analysis revealed very wide expression of both Fas and FasL. Several tissues, including the thymus, lung, spleen, small intestine, large intestine, seminal vesicle, prostate, and uterus, clearly coexpress the two genes. Most tissues constitutively coexpressing Fas and FasL in the adult mouse are characterized by apoptotic cell turnover, and many of those expressing FasL are known to be immune privileged. It may be, therefore, that the Fas system is implicated in both the regulation of physiological cell turnover and the protection of particular tissues against potential lymphocyte-mediated damage.

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Selected References

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  1. Alderson M. R., Tough T. W., Davis-Smith T., Braddy S., Falk B., Schooley K. A., Goodwin R. G., Smith C. A., Ramsdell F., Lynch D. H. Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med. 1995 Jan 1;181(1):71–77. doi: 10.1084/jem.181.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Belin D., Wohlwend A., Schleuning W. D., Kruithof E. K., Vassalli J. D. Facultative polypeptide translocation allows a single mRNA to encode the secreted and cytosolic forms of plasminogen activators inhibitor 2. EMBO J. 1989 Nov;8(11):3287–3294. doi: 10.1002/j.1460-2075.1989.tb08489.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bellgrau D., Gold D., Selawry H., Moore J., Franzusoff A., Duke R. C. A role for CD95 ligand in preventing graft rejection. Nature. 1995 Oct 19;377(6550):630–632. doi: 10.1038/377630a0. [DOI] [PubMed] [Google Scholar]
  4. Benedetti A., Jézéquel A. M., Orlandi F. Preferential distribution of apoptotic bodies in acinar zone 3 of normal human and rat liver. J Hepatol. 1988 Dec;7(3):319–324. doi: 10.1016/s0168-8278(88)80004-7. [DOI] [PubMed] [Google Scholar]
  5. Brunner T., Mogil R. J., LaFace D., Yoo N. J., Mahboubi A., Echeverri F., Martin S. J., Force W. R., Lynch D. H., Ware C. F. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature. 1995 Feb 2;373(6513):441–444. doi: 10.1038/373441a0. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Dhein J., Walczak H., Bäumler C., Debatin K. M., Krammer P. H. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95) Nature. 1995 Feb 2;373(6513):438–441. doi: 10.1038/373438a0. [DOI] [PubMed] [Google Scholar]
  8. French L. E., Chonn A., Ducrest D., Baumann B., Belin D., Wohlwend A., Kiss J. Z., Sappino A. P., Tschopp J., Schifferli J. A. Murine clusterin: molecular cloning and mRNA localization of a gene associated with epithelial differentiation processes during embryogenesis. J Cell Biol. 1993 Sep;122(5):1119–1130. doi: 10.1083/jcb.122.5.1119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. French L. E., Polla L. L., Tschopp J., Schifferli J. A. Membrane attack complex (MAC) deposits in skin are not always accompanied by S-protein and clusterin. J Invest Dermatol. 1992 May;98(5):758–763. doi: 10.1111/1523-1747.ep12499946. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Griffith T. S., Brunner T., Fletcher S. M., Green D. R., Ferguson T. A. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science. 1995 Nov 17;270(5239):1189–1192. doi: 10.1126/science.270.5239.1189. [DOI] [PubMed] [Google Scholar]
  12. Hahne M., Peitsch M. C., Irmler M., Schröter M., Lowin B., Rousseau M., Bron C., Renno T., French L., Tschopp J. Characterization of the non-functional Fas ligand of gld mice. Int Immunol. 1995 Sep;7(9):1381–1386. doi: 10.1093/intimm/7.9.1381. [DOI] [PubMed] [Google Scholar]
  13. Hofmann K., Tschopp J. The death domain motif found in Fas (Apo-1) and TNF receptor is present in proteins involved in apoptosis and axonal guidance. FEBS Lett. 1995 Sep 11;371(3):321–323. doi: 10.1016/0014-5793(95)00931-x. [DOI] [PubMed] [Google Scholar]
  14. Itoh N., Nagata S. A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen. J Biol Chem. 1993 May 25;268(15):10932–10937. [PubMed] [Google Scholar]
  15. Itoh N., Yonehara S., Ishii A., Yonehara M., Mizushima S., Sameshima M., Hase A., Seto Y., Nagata S. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991 Jul 26;66(2):233–243. doi: 10.1016/0092-8674(91)90614-5. [DOI] [PubMed] [Google Scholar]
  16. Kerr J. F., Searle J. Deletion of cells by apoptosis during castration-induced involution of the rat prostate. Virchows Arch B Cell Pathol. 1973 Jun 25;13(2):87–102. doi: 10.1007/BF02889300. [DOI] [PubMed] [Google Scholar]
  17. Kotzin B. L., Babcock S. K., Herron L. R. Deletion of potentially self-reactive T cell receptor specificities in L3T4-, Lyt-2- T cells of lpr mice. J Exp Med. 1988 Dec 1;168(6):2221–2229. doi: 10.1084/jem.168.6.2221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kägi D., Vignaux F., Ledermann B., Bürki K., Depraetere V., Nagata S., Hengartner H., Golstein P. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science. 1994 Jul 22;265(5171):528–530. doi: 10.1126/science.7518614. [DOI] [PubMed] [Google Scholar]
  19. Leithäuser F., Dhein J., Mechtersheimer G., Koretz K., Brüderlein S., Henne C., Schmidt A., Debatin K. M., Krammer P. H., Möller P. Constitutive and induced expression of APO-1, a new member of the nerve growth factor/tumor necrosis factor receptor superfamily, in normal and neoplastic cells. Lab Invest. 1993 Oct;69(4):415–429. [PubMed] [Google Scholar]
  20. Liu Y. J., Joshua D. E., Williams G. T., Smith C. A., Gordon J., MacLennan I. C. Mechanism of antigen-driven selection in germinal centres. Nature. 1989 Dec 21;342(6252):929–931. doi: 10.1038/342929a0. [DOI] [PubMed] [Google Scholar]
  21. Lowin B., Hahne M., Mattmann C., Tschopp J. Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature. 1994 Aug 25;370(6491):650–652. doi: 10.1038/370650a0. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Nagata S., Golstein P. The Fas death factor. Science. 1995 Mar 10;267(5203):1449–1456. doi: 10.1126/science.7533326. [DOI] [PubMed] [Google Scholar]
  24. Ogasawara J., Watanabe-Fukunaga R., Adachi M., Matsuzawa A., Kasugai T., Kitamura Y., Itoh N., Suda T., Nagata S. Lethal effect of the anti-Fas antibody in mice. Nature. 1993 Aug 26;364(6440):806–809. doi: 10.1038/364806a0. [DOI] [PubMed] [Google Scholar]
  25. Oppenheim R. W. Cell death during development of the nervous system. Annu Rev Neurosci. 1991;14:453–501. doi: 10.1146/annurev.ne.14.030191.002321. [DOI] [PubMed] [Google Scholar]
  26. Rotello R. J., Lieberman R. C., Lepoff R. B., Gerschenson L. E. Characterization of uterine epithelium apoptotic cell death kinetics and regulation by progesterone and RU 486. Am J Pathol. 1992 Feb;140(2):449–456. [PMC free article] [PubMed] [Google Scholar]
  27. Rozzo S. J., Eisenberg R. A., Cohen P. L., Kotzin B. L. Development of the T cell receptor repertoire in lpr mice. Semin Immunol. 1994 Feb;6(1):19–26. doi: 10.1006/smim.1994.1004. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Smith C. A., Farrah T., Goodwin R. G. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell. 1994 Mar 25;76(6):959–962. doi: 10.1016/0092-8674(94)90372-7. [DOI] [PubMed] [Google Scholar]
  30. Stathopoulos E., Naeve G. S., Taylor C. R., Epstein A. L. LN-6: a monoclonal antibody to vimentin expressed in non-hematopoietic mesenchymal cells and derived tumors and reactive in B5-fixed, paraffin-embedded tissues. J Histochem Cytochem. 1989 Sep;37(9):1363–1370. doi: 10.1177/37.9.2671152. [DOI] [PubMed] [Google Scholar]
  31. Steller H. Mechanisms and genes of cellular suicide. Science. 1995 Mar 10;267(5203):1445–1449. doi: 10.1126/science.7878463. [DOI] [PubMed] [Google Scholar]
  32. Streilein J. W. Unraveling immune privilege. Science. 1995 Nov 17;270(5239):1158–1159. doi: 10.1126/science.270.5239.1158. [DOI] [PubMed] [Google Scholar]
  33. Suda T., Okazaki T., Naito Y., Yokota T., Arai N., Ozaki S., Nakao K., Nagata S. Expression of the Fas ligand in cells of T cell lineage. J Immunol. 1995 Apr 15;154(8):3806–3813. [PubMed] [Google Scholar]
  34. 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]
  35. Surh C. D., Sprent J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature. 1994 Nov 3;372(6501):100–103. doi: 10.1038/372100a0. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. Tartaglia L. A., Ayres T. M., Wong G. H., Goeddel D. V. A novel domain within the 55 kd TNF receptor signals cell death. Cell. 1993 Sep 10;74(5):845–853. doi: 10.1016/0092-8674(93)90464-2. [DOI] [PubMed] [Google Scholar]
  38. Trauth B. C., Klas C., Peters A. M., Matzku S., Möller P., Falk W., Debatin K. M., Krammer P. H. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science. 1989 Jul 21;245(4915):301–305. doi: 10.1126/science.2787530. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. Watanabe-Fukunaga R., Brannan C. I., Itoh N., Yonehara S., Copeland N. G., Jenkins N. A., Nagata S. The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen. J Immunol. 1992 Feb 15;148(4):1274–1279. [PubMed] [Google Scholar]
  41. 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]

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