W111 - Loss of Thymic Tolerance to Perilipin-1 Is Associated with Adipose Autoimmunity in Aire-deficient Mice

Vera Tang – University of California, San Francisco; David Yu – University of California, San Francisco; Bin Zhang – Northeastern University; Abhimanyu Garg – University of Texas, Southwestern; Mark Anderson – University of California, San Francisco

Abstract Text: Acquired generalized lipodystrophy (AGL) is a clinical syndrome characterized by immune-mediated loss of body fat, hepatic steatosis and metabolic dysregulation. Recently, we reported autoantibodies to a lipid droplet protein, perilipin-1 (PLIN1) in patients with AGL as well as in humans and mice with defects in autoimmune regulator protein (AIRE), a master regulator of thymic tolerance to tissue antigens. Significantly, adipose tissue of Aire-/- mice showed profound mononuclear infiltrates, reminiscent of panniculitis observed in AGL. We thus sought to define the immunologic determinants of adipose autoimmunity in Aire-/- mice. We found that Plin1 was expressed by medullary thymic epithelial cells in wild type but not Aire-/- mice, suggesting that it is an Aire-dependent antigen. Aire-/- mice had dramatically reduced body fat stores and their livers showed evidence of microsteatosis, suggesting disrupted lipid metabolism, which are features of AGL. By flow cytometry, infiltrate in the Aire-/- fat pads was dominated by activated CD4 and CD8 T cells. To better understand immune populations involved in the attack on adipocytes, we performed single-cell RNA sequencing of the adipose CD45+ stromal vascular fraction. We observed a significant expansion of Th1-like and memory CD4 T cells and exhausted and memory CD8 T cells in the Aire-/- mice, consistent with an ongoing immune response. Furthermore, we have identified over 20 expanded T-cell clones, with current work ongoing to characterize their TCR specificities. Taken together, our data establish Aire-/- mice as a model of AGL and provide the first characterization of cellular heterogeneity in adipose autoimmunity.