Thymic expression of a gastritogenic epitope results in positive selection of self-reactive pathogenic T cells.
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.
Laurie
Karen L
KL
Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Australia. Division of Immunobiology, University of Bonn, Bonn, Germany.
La Gruta
Nicole L
NL
Koch
Norbert
N
van Driel
Ian R
IR
Gleeson
Paul A
PA
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D001324:Autoantigens / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003433:Crosses, Genetic; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis* / Q000378:metabolism; D005756:Gastritis / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D017506:H(+)-K(+)-Exchanging ATPase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007399:Interphase / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
D000944:Antigens, Differentiation, B-Lymphocyte; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D021122:Protein Subunits; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C045084:invariant chain; D017506:H(+)-K(+)-Exchanging ATPase