Thymic expression of a gastritogenic epitope results in positive selection of self-reactive pathogenic T cells
AuthorLaurie, KL; La Gruta, NL; Koch, N; van Driel, IR; Gleeson, PA
Source TitleJournal of Immunology
PublisherAMER ASSOC IMMUNOLOGISTS
AffiliationBiochemistry And Molecular Biology
Document TypeJournal Article
CitationsLaurie, K. L., La Gruta, N. L., Koch, N., van Driel, I. R. & Gleeson, P. A. (2004). Thymic expression of a gastritogenic epitope results in positive selection of self-reactive pathogenic T cells. JOURNAL OF IMMUNOLOGY, 172 (10), pp.5994-6002. https://doi.org/10.4049/jimmunol.172.10.5994.
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C1 - Journal Articles Refereed
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 beta subunit(253-277) (H/Kbeta(253-277)), was attached to the C terminus of the invariant chain (Ii) and the hybrid Ii (Ii-H/Kbeta(253-277)) expressed in mice under control of the Ii promoter. The Ii-H/Kbeta(253-277) fusion protein was localized to MHC class II-expressing cells in the thymus and periphery of Ii-H/Kbeta(253-277) transgenic mice. In one transgenic line the level of presentation in the periphery (spleen) was insufficient to activate naive, low affinity H/Kbeta(253-277)-specific transgenic T cells (1E4-TCR), whereas thymic presentation of H/Kbeta(253-277) enhanced positive selection of 1E4-TCR cells in Ii-H/Kbeta(253-277)/1E4-TCR double-transgenic mice. Furthermore, Ii-H/Kbeta(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/Kbeta(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.
KeywordsBiochemistry and Cell Biology not elsewhere classified ; Biological Sciences
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