Acquired Lipodystrophy is Mediated by a Treg Specific Deletion of Helios

Abstract

Abstract The selective deletion of the transcription factor, Helios, in Regulatory T Cells (Treg) leads to systemic immune activation characterized by a Th1 phenotype, hypergammaglobulinemia, and enhanced germinal center formation. Strikingly, we also observe acquired lipodystrophy, hepatic steatosis, and insulin resistance. Further analysis of the lipodystrophy had revealed a significant lymphocytic infiltrate in both the inguinal and perigonadal adipose tissue, indicating autoimmune mediated destruction of the white adipose tissue (WAT). We show here that the destruction of adipocytes is dependent on CD8 +T cells, as Helios fl/fl× Foxp3Cre mice crossed to B2m deficient mice (lacking Class I MHC) maintain normal adipose tissue volume. Flow cytometry analysis of the infiltrate demonstrates that the destruction of the adipose tissue is mediated by CD8 +T cells through both cytotoxic and Fas-L dependent mechanisms. Preliminary analysis of the adipose tissue Tregs suggests that the Treg fail to acquire or maintain an effector state in the absence of Helios. Thus, Helios deficiency in Treg disrupts immune homeostasis in the adipose tissue, leading to the expansion and activation of CD8 +T cells, the destruction of the tissue and metabolic disease. This work was supported by the Intramural Research Program of NIAID, NIH. This work was supported by the Intramural Research Program of NIAID, NIH.