Oral nickel tolerance: Fas ligand-expressing invariant NK T cells promote tolerance induction by eliciting apoptotic death of antigen-carrying, effete B cells

Michael Nowak, Frank Kopp, Karin Roelofs-Haarhuis, Xianzhu Wu, Ernst Gleichmann

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23 Scopus citations


Whereas oral nickel administration to C57BL/6 mice (Nihigh mice) renders the animals tolerant to immunization with NiCl2 combined with H2O2 as adjuvant, as determined by ear-swelling assay, it fails to tolerize Jα18-/- mice, which lack invariant NKT (iNKT) cells. Our previous work also showed that Nihigh splenic B cells can adoptively transfer the nickel tolerance to untreated (Ni low) recipients, but not to Jα18-/- recipients. In this study, we report that oral nickel administration increased the nickel content of splenic Nihigh 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 Jα18-/- Nihigh 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/H2O 2. As a consequence of immunization, Fas ligand-positive (FasL +) iNKT cells appeared in the spleen and apparently elicited apoptosis of Nihigh B cells. The apoptotic Nihigh B cells were taken up by splenic dendritic cells, which thereby became tolerogenic for nickel-reactive Nilow 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.

Original languageEnglish (US)
Pages (from-to)4581-4589
Number of pages9
JournalJournal of Immunology
Issue number8
Publication statusPublished - Apr 15 2006


All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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