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Oral Nickel Tolerance: Fas Ligand-Expressing Invariant NK T Cells Promote Tolerance Induction by Eliciting Apoptotic Death of Antigen-Carrying, Effete B Cells¹

Institut fuer umweltmedizinische Forschung at Heinrich Heine University, Duesseldorf, Germany

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 J18^–/– 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 J18^–/– 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-x_L, 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 J18^–/– 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.

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The JI 2006 176: 4507-4508. [Full Text]  

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