Oral nickel tolerance: Fas ligand-expressing invariant NK T cells promote tolerance induction by eliciting apoptotic death of antigen-carrying, effete B cells.
Whereas oral nickel administration to C57BL/6 mice (Ni(high) mice) renders the animals tolerant to immunization with NiCl2 combined with H2O2 as adjuvant, as determined by ear-swelling assay, it fails to tolerize Jalpha18-/- mice, which lack invariant NKT (iNKT) cells. Our previous work also showed that Ni(high) splenic B cells can adoptively transfer the nickel tolerance to untreated (Ni(low)) recipients, but not to Jalpha18-/- recipients. In this study, we report that oral nickel administration increased the nickel content of splenic Ni(high) B cells and up-regulated their Fas expression while down-regulating expression of bcl-2 and Bcl-xL, thus giving rise to an Ag-carrying, apoptosis-prone B cell phenotype. Although oral nickel up-regulated Fas expression on B cells of both wild-type Ni(high) and Jalpha18-/- Ni(high) mice, only the former showed a reduced number of total B cells in spleen when compared with untreated, syngeneic mice, indicating that iNKT cells are involved in B cell homeostasis by eliciting apoptosis of effete B cells. Upon transfer of Ni(high) B cells, an infectious spread of nickel tolerance ensues, provided the recipients are immunized with NiCl2/H2O2. As a consequence of immunization, Fas ligand-positive (FasL+) iNKT cells appeared in the spleen and apparently elicited apoptosis of Ni(high) B cells. The apoptotic Ni(high) B cells were taken up by splenic dendritic cells, which thereby became tolerogenic for nickel-reactive Ni(low) T cells. In conclusion, FasL+ iNKT cells may act as ready-to-kill sentinels of innate immunity, but at the same time assist in tolerance induction by eliciting Fas/FasL-mediated apoptosis of effete, Ag-containing B cells.
Institut fuer umweltmedizinische Forschung at Heinrich Heine University, Duesseldorf, Germany. michael.nowak@uni-duesseldorf.de
Michael
M
Nowak
Frank
F
Kopp
Karin
K
Roelofs-Haarhuis
Xianzhu
X
Wu
Ernst
E
Gleichmann
D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D053222:Fas Ligand Protein; D005260:Female; D007108:Immune Tolerance; D007694:Killer Cells, Natural / Q000145:classification / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D018448:Models, Immunological; D009532:Nickel / Q000008:administration & dosage* / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors; D019014:fas Receptor; D009532:Nickel