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International Immunology, Vol. 12, No. 3, 343-352, March 2000
© 2000 Japanese Society for Immunology

Tolerance and autoimmunity to a gastritogenic peptide in TCR transgenic mice

Frank Alderuccio, Valenzio Cataldo, Ian R. van Driel, Paul A. Gleeson and Ban Hock Toh

Department of Pathology and Immunology, Monash University Medical School, Commercial Road, Prahran, Victoria 3181, Australia

Correspondence to: F. Alderuccio

The catalytic {alpha} and glycoprotein ß subunits of the gastric H/K ATPase are major molecular targets in human and mouse autoimmune gastritis. We have previously shown that the H/K ATPase ß subunit is required for the initiation of mouse gastritis and identified a gastritogenic H/K ATPase ß subunit peptide (H/Kß253–277). Here we report the generation of MHC class II-restricted TCR transgenic mice using V{alpha}9 and Vß8.3 TCR chains with specificity for the gastritogenic H/Kß253–277 peptide. We found an 8-fold reduction in CD4+ T cells in the thymus of the transgenic mice. Despite the reduction in intrathymic CD4+ T cells, Vß8.3-expressing T cells comprised the majority (>90%) of peripheral spleen and lymph node T cells. These peripheral T cells retained their capacity to proliferate in vitro to the H/Kß253–277 peptide. Using the responsive T cells, we have restricted the gastritogenic T cell epitope to H/Kß261–274. Despite the capacity of the peripheral T cells to proliferate in vitro to the peptide, the majority (~80%, 13 of 16) of transgenic mice remained free of gastritis while a minority (20%, three of 16) spontaneously developed an invasive and destructive gastritis. Our results confirm that H/Kß261–274 is a gastritogenic peptide. The data also suggest that CD4 T cell tolerance to the gastritogenic peptide in the transgenic mice is maintained by a combination of intrathymic and peripheral tolerance mechanisms.

Keywords: autoimmunity, T lymphocytes, TCR, transgenic mice

Transmitting editor: D. Tarlinton


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