A Treg-specific deletion of Helios causes autoimmune lipodystrophy and metabolic syndrome

Abstract

Abstract Regulatory T (Treg) cells suppress immune activation in a dominant manner and play a critical role in the maintenance of self-tolerance. A subpopulation (60–75%) of Foxp3+T regulatory (Treg) cells express the transcription factor Helios. To examine the function of Helios in Treg cells, we have generated Treg-specific Helios deficient mice (cKO, Heliosflxflx Foxp3cre). Although both Treg development in the cKO mice and their in vitro suppressor function are normal, the selective deletion of Helios in Tregs leads to slow, progressive systemic immune activation with a Th1 phenotype, hypergammaglobulinemia, and enhanced germinal center formation. Initially, we observed significant lymphocytic infiltrates only in the salivary gland and not in any other organs typically affected by Treg dysregulation. Strikingly, the mice developed lipodystrophy, hepatic steotosis and insulin resistance. Further analysis revealed a significant lymphocytic infiltrate in both the inguinal and perigonadal adipose tissue, indicating autoimmune mediated destruction of the white adipose tissue (WAT). We have further shown that the lymphocytic infiltrate specific to WAT can be transferred from mice with lipodystrophy to immunodeficient mice, confirming the autoimmune nature of the lipodystrophy. Thus, Helios deficiency in Treg disrupts immune homeostasis in the adipose tissue, leading to the destruction of WAT and redirection of lipids to the liver, and ultimately causes metabolic dysfunction. Supported by the Intramural Research Program of the NIAID, NIH.