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.

Abbreviations used in this paper: H⁺/K⁺ ATPase, gastric H⁺/K⁺ ATPase encoded by Atp4a and Atp4b, H/Kα, H⁺/K⁺ ATPase α subunit encoded by Atp4a, H/Kβ, the H⁺/K⁺ ATPase β subunit encoded by Atp4b, T_reg cells, CD4⁺CD25⁺Foxp3⁺ regulatory T cells, H/Kα^−/−, H/Kα−deficient, H/Kβ^−/−, H/Kβ−deficient, BALB/c-CD90.1, CByJ.PL(B6)-Thy1^a/ScrJ, BALB/c^nu, athymic CByJ.Cg-Foxn1^nu, CFSE, carboxyfluoroscein succinimydyl ester, CFSE, carboxyfluoroscein succinimydyl ester, TCR, T cell receptor, WT, wild-type