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Endogenous H/K ATPase -Subunit Promotes T Cell Tolerance to the Immunodominant Gastritogenic Determinant¹

Karen L. Laurie^*, Ian R. van Driel^*, Tricia D. Zwar^*, Simon P. Barrett and Paul A. Gleeson^2,*

^* Department of Biochemistry and Molecular Biology, University of Melbourne, and Department of Pathology and Immunology, Monash University Medical School, Melbourne, Victoria, Australia

A CD4⁺ T cell response to the gastric H/K ATPase -subunit (H/K) is required for the onset of experimental autoimmune gastritis in BALB/c mice. The extent to which endogenous H/K contributes toward the tolerance of the H/K-specific T cell repertoire in normal individuals is not known. By comparison of T cell responses in H/K-deficient (o/o) and H/K-expressing BALB/c mice, in this work we show that the endogenous H/K autoantigen plays a major role in the tolerance of pathogenic H/K-specific T cells. First, T cell-dependent Ab responses to the H/K Ag were enhanced in H/K ATPase-immunized H/K-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/K_253–277, were significantly more vigorous in H/K-deficient mice compared with wild-type mice. Third, unfractionated splenocytes from H/K-deficient mice, but not H/K-expressing mice, induced autoimmune gastritis after adoptive transfer to BALB/c nude mice. The enhanced responses to H/K in H/K-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/K-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.

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