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/K alpha) and beta (H/K beta) subunits of the gastric membrane protein the H+/K+ ATPase. H/K alpha mRNA is expressed in the thymus, but H/K beta expression is barely detectable. In this study,me demonstrate that thymic H/K alpha in wild-type mice or mice that overexpressed H/K alpha did not result in negative selection of pathogenic anti-H/K alpha T cells. However, negative selection of anti-H/K alpha T cells did occur if H/K beta was artificially overexpressed in the thymus. Given that H/K alpha cannot be exported from the endoplasmic reticulum and is rapidly degraded in the absence of H/K beta, we conclude that H/K alpha 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.