Prevention of Autoimmune Gastritis in Mice Requires Extra-Thymic T-Cell Deletion and Suppression by Regulatory T Cells

Background & Aims: Autoimmune gastritis is one of the most common autoimmune diseases and is caused by a CD4 + T-cell response to the gastric H + /K + ATPase encoded by Atp4a and Atp4b (H + /K + ATPase). Here, we have elucidated events that result in immunological tolerance to the H + /K + ATPase and thus the prevention of autoimmune gastritis. Methods: T cells from H + /K + ATPase–deficient mice and H + /K + ATPase–specific T-cell receptor transgenic mice were purified and transferred to wild-type (WT) or H + /K + ATPase–deficient recipients to assess the impact of exposure to antigen on pathogenicity. Results: The CD4 + T-cell population from H + /K + ATPase–deficient mice was highly effective at inducing gastritis when compared with T cells from WT mice and, as a population, was comparatively resistant to the suppressive activity of regulatory T cells. Exposing T cells from H + /K + ATPase–deficient mice to H + /K + ATPase in WT mice decreased their ability to induce gastritis and resulted in a population that could be more easily suppressed by T reg cells. Transfer of clonotypic antigen-inexperienced H + /K + ATPase–specific T cells into WT mice resulted in extra-thymic clonal deletion. Conclusions: Prevention of autoimmune gastritis requires the extra-thymic purging of highly autoaggressive H + /K + ATPase–specific T cells to produce a T-cell repertoire that is more susceptible to the suppressive activity of regulatory T cells. Taken together with recent published data describing the role of T-cell receptor signalling in the maintenance of regulatory T-cell populations, we propose that exposure of T cells to antigen in the periphery is able to both delete autoaggressive specificities and maintain regulatory T-cell activity, establishing a balance between pathogenicity and regulation.