Transgenic expression of Fas ligand on thyroid follicular cells prevents autoimmune thyroiditis.
"Immune privilege" is defined as tissue resistance to aggression by specifically activated lymphocytes, and involves the interaction between Fas expressed on infiltrating cells and Fas ligand (FasL) constitutively expressed on the target tissue. To test whether ectopic expression of FasL on thyrocytes could prevent autoimmune aggression of the thyroid by activated lymphoid cells, three lines of transgenic mice expressing low, intermediate, and high levels of functional FasL on thyroid follicular cells were generated. Experimental autoimmune thyroiditis was induced by immunization with mouse thyroglobulin. In all of the experiments, the effects were dependent on the level of FasL expression. Low and intermediate expression had no or only weak preventive effects, respectively, whereas high FasL expression strongly inhibited lymphocytic infiltration of the thyroid. Anti-mouse thyroglobulin-proliferative and cytotoxic T cell responses, as well as autoantibody production, were diminished in transgenic mice expressing high levels of FasL relative to controls. Furthermore, in these latter mice Th1 responses to mouse thyroglobulin were profoundly down-regulated, uncovering a new potential role for FasL in peripheral tolerance to organ-specific Ags. In sum, the prevention of experimental autoimmune thyroiditis by FasL on thyrocytes is dependent on the level of FasL expression.
Batteux
F
F
Institut National de la Santé et de la Recherche Médicale (INSERM) U477, Université René Descartes, Paris, France.
Lores
P
P
Bucchini
D
D
Chiocchia
G
G
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D053222:Fas Ligand Protein; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007271:Injections, Intradermal; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013954:Thyroglobulin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D013961:Thyroid Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D013967:Thyroiditis, Autoimmune / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007074:Immunoglobulin G; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor; D007371:Interferon-gamma; D013954:Thyroglobulin