Tolerance and autoimmunity to a gastritogenic peptide in TCR transgenic mice

The catalytic alpha and glycoprotein beta subunits of the gastric H/K ATPas e are major molecular targets in human and mouse autoimmune gastritis, We h ave previously shown that the H/K ATPase beta subunit is required for the i nitiation of mouse gastritis and identified a gastritogenic H/K ATPase beta subunit peptide (H/K beta 253-277). Here we report the generation of MHC c lass Ii-restricted TCR transgenic mice using V(alpha)9 and V(beta)8.3 TCR c hains with specificity for the gastritogenic H/K beta 253-277 peptide. We f ound an 8-fold reduction in CD4(+) T cells in the thymus of the transgenic mice. Despite the reduction in intrathymic CD4(+) T cells, V(beta)8.3-expre ssing T cells comprised the majority (>90%) of peripheral spleen and lymph node T cells. These peripheral T cells retained their capacity to prolifera te in vitro to the H/K beta 253-277 peptide. Using the responsive T cells, we have restricted the gastritogenic T cell epitope to HIK beta 261-274. De spite the capacity of the peripheral T cells to proliferate in vitro to the peptide, the majority (similar to 80%, 13 of 16) of transgenic mice remain ed free of gastritis while a minority (20%, three of 16) spontaneously deve loped an invasive and destructive gastritis, Our results confirm that H/K b eta 261-274 is a gastritogenic peptide. The data also suggest that CD4 T ce ll tolerance to the gastritogenic peptide in the transgenic mice is maintai ned by a combination of intrathymic and peripheral tolerance mechanisms.