Uptake of apoptotic antigen-coupled cells by lymphoid dendritic cells and cross-priming of CD8(+) T cells produce active immune unresponsiveness.
The induction of immunologic unresponsiveness by i.v. administration of Ag-coupled lymphoid cells has been studied extensively, but the mechanisms remain unclear. We have further explored this model by examining the role of Fas/Fas ligand (FasL)-mediated apoptosis. Using i.v. injection of trinitrophenyl-coupled splenocytes (TNP-spl) as tolerogen, we found that Fas signaling for apoptosis in the spleen cells delivered by FasL in the recipient is the critical event. The requirement for Fas and FasL was overcome by prior induction of apoptosis in TNP-spl, making the tolerogen 100 times more potent. Prevention of apoptosis by a caspase inhibitor blocks tolerance. Interestingly, while blocking CD40/CD40 ligand interaction does not prevent tolerance induction, an agonist anti-CD40 Ab turns tolerogenic TNP-spl into an immunizing Ag. Studies further showed that tolerance is induced through cross-presentation of Ag in a class I MHC-dependent manner by CD8(+)CD11c(+) lymphoid-derived dendritic cells to regulatory T cells. The results provide a mechanism for a well-established method of inducing immunologic unresponsiveness.
Ferguson
Thomas A
TA
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA. Ferguson@vision.wustl.edu
Herndon
John
J
Elzey
Bennett
B
Griffith
Thomas S
TS
Schoenberger
Steve
S
Green
Douglas R
DR
D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000276:immunology*; D017209:Apoptosis; D019013:CD40 Antigens / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000502:physiology*; D053222:Fas Ligand Protein; D015395:Histocompatibility Antigens Class I / Q000502:physiology; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D019014:fas Receptor / Q000502:physiology
D000941:Antigens; D019013:CD40 Antigens; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D019014:fas Receptor