CD4+CD25+ regulatory T cells inhibit the antigen-dependent expansion of self-reactive T cells in vivo

A deficiency of CD4(+)CD25(+) regulatory T cells (CD25(+) Tregs) in lymphopenic mice can result in the onset of autoimmune gastritis. The gastric H/K ATPase a (H/K alpha) and beta (H/K beta) subunits are the immunodominant autoantigens recognized by effector CD4(+) T cells in autoimmune gastritis. The mechanism by which CD25(+) Tregs suppress autoimmune gastritis in lymphopenic mice is poorly understood. To investigate the antigenic requirements for the genesis and survival of gastritis-protecting CD25(+) Tregs, we analyzed mice deficient in H/K beta and H/K alpha, as well as a transgenic mouse line (H/K beta-tsA58 Tg line 224) that lacks differentiated gastric epithelial cells. By adoptive transfer of purified T cell populations to athymic mice, we show that the CD25(+) Treg population from mice deficient in either one or both of H/K alpha and H/K beta, or from the H/K beta-tsA58 Tg line 224 mice, is equally effective in suppressing the ability of polyclonal populations of effector CD4(+) T cells to induce autoimmune gastritis. Furthermore, CD25(+) Tregs, from either wild-type or H/K alpha-deficient mice, dramatically reduced the expansion of pathogenic H/K alpha-specific TCR transgenic T cells and the induction of autoimmune gastritis in athymic recipient mice. Proliferation of H/K alpha-specific T cells in lymphopenic hosts occurs predominantly in the paragastric lymph node and was dependent on the presence of the cognate H/Ka Ag. Collectively, these studies demonstrate that the gastritis-protecting CD25(+) Tregs do not depend on the major gastric Ags for their thymic development or their survival in the periphery, and that CD25(+) Tregs inhibit the Ag-specific expansion of pathogenic T cells in vivo.