Oral Tolerance to Nickel Requires CD4+ Invariant NKT Cells for the Infectious Spread of Tolerance and the Induction of Specific Regulatory T Cells

Abstract

Previously, oral administration of nickel to C57BL/6 wild-type (WT) mice was shown to render both their splenic T cells and APCs (i.e., T cell-depleted spleen cells) capable of transferring nickel tolerance to naive syngeneic recipients. Moreover, sequential adoptive transfer experiments revealed that on transfer of tolerogenic APCs and immunization, the naive T cells of the recipients differentiated into regulatory T (Treg) cells. Here, we demonstrate that after oral nickel treatment Jalpha18(-/-) mice, which lack invariant NKT (iNKT) cells, were not tolerized and failed to generate Treg cells. However, transfer of APCs from those Jalpha18(-/-) mice did tolerize WT recipients. Hence, during oral nickel administration, tolerogenic APCs are generated that require iNKT cell help for the induction of Treg cells. To obtain this help, the tolerogenic APCs must address the iNKT cells in a CD1-restricted manner. When Jalpha18(-/-) mice were used as recipients of cells from orally tolerized WT donors, the WT Treg cells transferred the tolerance, whereas WT APCs failed to do so, although they proved tolerogenic on transfer to WT recipients. However, Jalpha18(-/-) recipients did become susceptible to the tolerogenicity of transferred WT APCs when they were reconstituted with IL-4- and IL-10-producing CD4(+) iNKT cells. We conclude that CD4(+) iNKT cells are required for the induction of oral nickel tolerance and, in particular, for the infectious spread of tolerance from APCs to T cells. Once induced, these Treg cells, however, can act independently of iNKT cells.

Clinical immunology Th1 and Th2 cytokine profile of CD4 and CD8 positive peripheral blood lymphocytes in nickel contact dermatitis

“…In addition animal studies involving the induction of nickel tolerance by prolonged oral contact have shown that the key cytokine involved in the nickel tolerance is IL-10. Based on these observations production of IL-10 in response to nickel challenge has been proposed as a test for identification of nickel tolerized individuals [30,31]. The presence of a significantly higher percentage of IL-10 producing cells in the peripheral blood of patch test negative otherwise normal individuals in the present study is in agreement with the protective role of IL-10 against development of CD.…”

Splenocyte Cytokine Profile in Mouse with Oral Mucosa-sensitization and Oral-tolerization by NiSO4

“…In our experiment, only a total of 1M nickel induced tolerance by single oral administration, indicating that oral tolerance to nickel can be achieved at a lower concentration than suggested in earlier reports 12,15,19) . In a sensitization study using painting with picryl chloride, ear swelling was suppressed by single oral administration in skin-sensitized mice 1) .…”

“…Weaker swelling in the oral-sensitization mice may be due to the lower number of Langerhans' cells, as in the case of DNCB 13) . In previous reports, oral tolerance was successfully induced in mice by drinking water containing 9M NiSO 4 for 1 week or 10 mM NiCl 2 for 4 weeks 12,15,19) . We found that immunologic tolerance to nickel could only be induced by single oral administration.…”

“…A total of 1.1 mM nickel was taken up by mice drinking 10 mM NiCl 2 -containing water over 4 weeks in a previous report 12,15) . In our experiment, only a total of 1M nickel induced tolerance by single oral administration, indicating that oral tolerance to nickel can be achieved at a lower concentration than suggested in earlier reports 12,15,19) .…”

CD38 Is Required for the Peripheral Survival of Immunotolerogenic CD4+ Invariant NK T Cells in Nonobese Diabetic Mice

“…Such disease acceleration could also at least be partly due to a loss in Treg numbers or function previously shown to be elicited by DCs in a NKT cell-dependent fashion (45). Indeed, a loss of iNKT cells may also contribute to the decreased levels of Tregs we previously observed in NOD.CD38 null mice (27).…”