Dose dependence of oral tolerance to nickel

The dose dependence of oral nickel tolerance was analyzed by comparing three different subsets of C57BL/6 mice: Ni^{very low} mice were reared in a nickel-reduced environment, Ni^low and Ni^high mice were reared in a stainless steel-containing environment and the latter received oral NiCl₂ (10 mM). In spleen and feces, Ni^{very low} mice exhibit significantly lower nickel concentrations than Ni^low and Ni^high mice. In contrast to Ni^{very low} mice that can be sensitized with a single intradermal administration of NiCl₂ alone, Ni^low mice can only be sensitized in the presence of an adjuvant and Ni^high mice cannot be sensitized at all. This dose-dependent resistance to nickel sensitization (i.e. Ni^high > Ni^low> Ni^{very low}) correlates with differences in the number and type of nickel-specific T regulatory (Treg) cells. Adoptive transfer studies into Ni^{very low} recipients showed that Ni^{very low} mice completely lack specific Treg cells whereas Ni^low and Ni^high mice harbor them, albeit their numbers and/or suppressive strength are much higher in Ni^high than Ni^low mice. The principal Treg subset in Ni^low mice consists of CD4⁺CD25 cells, among which CD4⁺CD25⁺ α_Eβ7⁺ cells are the most effective. In Ni^high mice, CD4⁺CD25⁺ Treg cells co-exist with an ensemble of CD8⁺ Treg and CD4⁺ CD25^- suppressor-inducer cells.