Regulatory T-cells in the hypothalamus control immune activation and improve metabolic impairments upon high-calorie environments

The hypothalamus in the central nervous system (CNS) plays a key role in the control of systemic metabolism. A calorie-rich diet triggers CNS immune activation, which contributes to impairments of metabolic control, favoring obesity and Type 2 Diabetes (T2D). However, cell types and molecular processes regulating hypothalamic immune activation remain incompletely understood. Here, we report the functionally relevant presence of regulatory T cells (Tregs), key players in the control of immune and tissue homeostasis, in the hypothalamus. Exposure to calorie-rich environments triggers immune activation of hypothalamic CD4+T cells, infiltrating macrophages and microglia while decreasing the presence of hypothalamic Tregs in mice. mRNA expression profiling of hypothalamic CD4+T cells revealed a Th1-like activation state evidenced by high levels of Tbx21, Cxcr3 and Cd226 and a decrease of Ccr7 and S1pr1 expression, a profile typical for recruitment of T cells to and retention at inflammatory sites. Importantly, mechanistic Treg loss- and gain-of-function experiments in vivo, show that Foxp3+Tregs limit hypothalamic immune activation and improve metabolic impairments induced by hyper-caloric feeding. Our findings refine the current model of immuno-metabolic crosstalk in the brain in response to environmental challenges and are of relevance for the future development of immune interventions to support health in obesity and T2D. Foxp3 GFP reporter mice were fed a high-fat high-sugar diet (HFHSD) or a standard diet (SD) for the indicated time points. Additionally, genetically obese ob/ob mice vs. BL6J mice were used. Cells from brains or hypothalami were isolated by homogenization and stained for FACS, followed by sorting of the indicated T cell subsets for purity. Bulk RNA-seq was performed.