Promiscuous thymic expression of an autoantigen gene does not result in negative selection of pathogenic T cells.
"Promiscuous" thymic expression of peripheral autoantigens can contribute to immunological tolerance in some cases. However, in this study we show that thymic mRNA expression alone cannot predict a contribution to thymic tolerance. Autoimmune gastritis is caused by CD4+ T cells directed to the alpha (H/Kalpha) and beta (H/Kbeta) subunits of the gastric membrane protein the H+/K+ ATPase. H/Kalpha mRNA is expressed in the thymus, but H/Kbeta expression is barely detectable. In this study, we demonstrate that thymic H/Kalpha in wild-type mice or mice that overexpressed H/Kalpha did not result in negative selection of pathogenic anti-H/Kalpha T cells. However, negative selection of anti-H/Kalpha T cells did occur if H/Kbeta was artificially overexpressed in the thymus. Given that H/Kalpha cannot be exported from the endoplasmic reticulum and is rapidly degraded in the absence of H/Kbeta, we conclude that H/Kalpha epitopes are unable to access MHC class II loading compartments in cells of the normal thymus. This work, taken together with our previous studies, highlights that thymic autoantigen expression does not necessarily result in the induction of tolerance.
Allen
Stacey
S
Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia.
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Simon
S
DiPaolo
Richard
R
McHugh
Rebecca S
RS
Shevach
Ethan M
EM
Gleeson
Paul A
PA
van Driel
Ian R
IR
D000818:Animals; D001324:Autoantigens / Q000235:genetics*; D001327:Autoimmune Diseases / Q000209:etiology; D015704:CD4 Antigens / Q000235:genetics; D005756:Gastritis / Q000209:etiology; D017506:H(+)-K(+)-Exchanging ATPase / Q000032:analysis / Q000235:genetics*; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D021122:Protein Subunits; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*
D001324:Autoantigens; D015704:CD4 Antigens; D021122:Protein Subunits; D011948:Receptors, Antigen, T-Cell; D017506:H(+)-K(+)-Exchanging ATPase