Normal induction of oral tolerance in the absence of a functional IL-12-dependent IFN-gamma signaling pathway.

There is considerable evidence that regulatory cytokines play an important role in mediating the systemic tolerance found after oral administration of protein Ags. Although most existing work has focused on cytokines such as IL-4, IL-10, and TGF-beta, recent evidence from TCR transgenic systems suggests that the induction of oral tolerance is accompanied by priming of Ag-specific IFN-gamma production. IFN-gamma has also been implicated as a mediator of T cell tolerance in other models in vivo and in vitro, including that induced by aerosol administration of protein. We show here that feeding tolerogenic doses of OVA primes for IFN-gamma production in the spleen of mice with a normal T cell repertoire. However, depleting IFN-gamma at the time of feeding OVA had no effect on the induction of tolerance. In addition, tolerance was induced normally in both IFN-gamma receptor knockout (IFN-gammaR-/-) and IL-12 p40 knockout (IL-12-/-) mice. This was the case for all components of the systemic immune response and also with a variety of feeding protocols, including those believed to induce distinct regulatory mechanisms. We conclude that IL-12-dependent IFN-gamma-mediated regulation does not play an essential role in oral tolerance.