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Thymic Expression of a Gastritogenic Epitope Results in Positive Selection of Self-Reactive Pathogenic T Cells¹

Karen L. Laurie^2,*, Nicole L. La Gruta^2,3,*, Norbert Koch, Ian R. van Driel^* and Paul A. Gleeson^4,*

^* Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Australia; and Division of Immunobiology, University of Bonn, Bonn, Germany

Intrathymic expression of tissue-specific self-Ags can mediate tolerance of self-reactive T cells. However, in this study we define circumstances by which thymic expression of a tissue-specific autoepitope enhances positive selection of disease-causing, self-reactive T cells. An immunodominant gastritogenic epitope, namely the gastric H/K ATPase subunit_253–277 (H/K_253–277), was attached to the C terminus of the invariant chain (Ii) and the hybrid Ii (Ii-H/K_253–277) expressed in mice under control of the Ii promoter. The Ii-H/K_253–277 fusion protein was localized to MHC class II-expressing cells in the thymus and periphery of Ii-H/K_253–277 transgenic mice. In one transgenic line the level of presentation in the periphery (spleen) was insufficient to activate naive, low affinity H/K_253–277-specific transgenic T cells (1E4-TCR), whereas thymic presentation of H/K_253–277 enhanced positive selection of 1E4-TCR cells in Ii-H/K_253–277/1E4-TCR double-transgenic mice. Furthermore, Ii-H/K_253–277/1E4-TCR double-transgenic mice had an increased incidence of autoimmune gastritis compared with 1E4-TCR single-transgenic mice, demonstrating that the 1E4 T cells that seeded the periphery of Ii-H/K_253–277 mice were pathogenic. Therefore, low levels of tissue-specific Ags in the thymus can result in positive selection of low avidity, self-reactive T cells. These findings also suggest that the precise level of tissue-specific Ags in the thymus may be an important consideration in protection against autoimmune disease and that perturbation of the levels of self-Ags may be detrimental.

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