Induction of specific T cell tolerance by Fas ligand-expressing antigen-presenting cells.
Autocrine interaction of Fas and Fas ligand leads to apoptosis of activated T cells, a process that is critical for the maintenance of peripheral T cell tolerance. Paracrine interactions of Fas ligand with T cells also may play an important role in the maintenance of tolerance, as Fas ligand can create immune-privileged sites and prevent graft rejection by inducing apoptosis in T cells. We surmised that APCs that express Fas ligand might directly induce apoptosis of T cells during presentation of Ag to the T cells, thus inducing Ag-specific, systemic T cell tolerance. Here, we show that profound, specific T cell unresponsiveness to alloantigen was induced by treatment of H-2k mice with H-2b APCs that expressed Fas ligand and that profound T cell unresponsiveness specific for the H-Y Ag was induced by treatment of H-2Db/H-Y TCR transgenic female mice with H-2Db/H-Y APCs that expressed Fas ligand. The induction of this systemic T cell tolerance required the expression of Fas ligand on the APCs as well as the expression of Fas on the T cells. The tolerance was restricted to the Ag presented by the APCs. The rapid and profound clonal deletion of the Ag-specific, peripheral T cells mediated by the Fas ligand-expressing APCs contributed to the induction of tolerance. These findings demonstrate that Ag-specific T cell tolerance can be induced by APCs that express Fas ligand and suggest a novel function for APCs in the induction of T cell apoptosis. Furthermore, they indicate a novel immunointervention strategy for treatment of graft rejection and autoantigen-specific autoimmune diseases.
Zhang
H G
HG
Division of Clinical Immunology and Rheumatology, University of Alabama, Birmingham, AL 35294, USA.
Su
X
X
Liu
D
D
Liu
W
W
Yang
P
P
Wang
Z
Z
Edwards
C K
CK
Bluethmann
H
H
Mountz
J D
JD
Zhou
T
T
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D053222:Fas Ligand Protein; D005260:Female; D006183:H-2 Antigens; D006182:H-Y Antigen; D007108:Immune Tolerance; D007519:Isoantigens; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019014:fas Receptor / Q000378:metabolism