Identification of T cell autoantigens in a mouse model of lupus nephritis 3880

Abstract Description Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune disease characterized by loss of tolerance to self-antigens. Autoreactive CD4+ T cells play a key role in SLE, but the mechanism of loss of self-tolerance and their antigen specificity is unclear. We aimed to profile the antigenic landscape of SLE in order to understand the key underlying biology of CD4+ T cells in promoting disease. To that end, we used MRL/lpr mice that spontaneously develop nephritis, and profiled their kidney immunopeptidome. We affinity-purified pMHC complexes from kidneys of young and old MRL/lpr mice, eluted MHC-bound peptides, and identified them using mass spectrometry. We identified shared and unique peptides presented in young and old mice and peptides that undergo age-associated increase in abundance. RNA-seq on CD45 depleted kidneys from MRL/lpr mice showed that while potential autoantigens and antigen-processing and presentation pathways were upregulated with age, there was a distinct lack of co-stimulatory molecules. We also profiled kidney-infiltrating T cells by scRNA-seq and high throughput T cell receptor cloning. We identified ∼50 clonally expanded kidney-infiltrating TCRs. We are currently using our laboratory’s antigen discovery platform to identify autoantigens recognized by them. The current study will identify key autoantigens driving SLE pathology and provide groundwork for development of novel disease biomarkers, and identify potential immunotherapy targets. Topic Categories Basic Autoimmunity (BA)