Perp Deficiency Induces Defective Negative Selection and Autoimmune Arthritis in Aged Mice

Thymic negative selection is characterized by the apoptosis of autoreactive thymocytes and plays a critical role in maintaining self-tolerance. Numerous apoptosis-related genes influence cell fate during T-cell development. The PERP protein functions in apoptosis induction and as a tumor suppressor; however, p53 targets the Perp promoter, leading to its downregulation in various cancers. We investigated the specific role of Perp by studying conditional knock-out mice exhibiting partial thymic T-cell development defects and a significant accumulation of thymic CD4SP T-cells. Ex vivo and in vivo analyses revealed that Perp regulates the survival of thymic T-cell subsets during clonal deletion, particularly CD4SP T-cells following TCR stimulation. These floxed mice also exhibited an expansion of the Helios⁺ CD4SP thymocyte population. Moreover, middle-aged floxed mice exhibited excessive accumulation of activated CD4⁺ T-cells in peripheral blood, alongside T cell-mediated autoimmune arthritis. These findings indicate that conditional Perp knockout mice exhibit a deficiency in thymic negative selection and heightened susceptibility to autoimmunity with aging.