Endogenous H/K ATPase β-subunit promotes T cell tolerance to the immunodominant gastritogenic determinant

A CD4⁺ T cell response to the gastric H/K ATPase β-subunit (H/Kβ) is required for the onset of experimental autoimmune gastritis in BALB/c mice. The extent to which endogenous H/Kβ contributes toward the tolerance of the H/Kβ-specific T cell repertoire in normal individuals is not known. By comparison of T cell responses in H/Kβ-deficient (o/o) and H/Kβ-expressing BALB/c mice, in this work we show that the endogenous H/Kβ autoantigen plays a major role in the tolerance of pathogenic H/Kβ-specific T cells. First, T cell-dependent Ab responses to the H/Kβ Ag were enhanced in H/K ATPase-immunized H/Kβ-deficient mice compared with wild-type mice. Second, peptide immunization experiments indicated that immune responses to the major gastritogenic epitope of the H/K ATPase, namely H/Kβ_253-277, were significantly more vigorous in H/Kβ-deficient mice compared with wild-type mice. Third, unfractionated splenocytes from H/Kβ-deficient mice, but not H/Kβ-expressing mice, induced autoimmune gastritis after adoptive transfer to BALB/c nude mice. The enhanced responses to H/Kβ in H/Kβ-deficient mice were shown to be intrinsic to CD4⁺CD25^- T cells rather than a change in status of CD4⁺CD25⁺ regulatory T cells. We conclude from these studies that the H/Kβ-specific T cells in wild-type mice represent the residue of a T cell repertoire, directed toward a single determinant, that has been subjected to partial tolerance induction.