Regulatory T cells in the mouse hypothalamus control immune activation and ameliorate metabolic impairments in high-calorie environments
Maike Becker, Stefanie Kälin, Anne H. Neubig, Michael Lauber, Daria Opaleva, Hannah Hipp, Victoria K. Salb, Verena B. Ott, Beata Legutko, Roland E. Kälin, Markus Hippich, Martin G. Scherm, Lucas F. Nascimento, Isabelle Serr, Fabian Hosp, Alexei Nikolaev, Alma N. Mohebiany, Martin Krueger, Bianca Flachmeyer, Michael W. Pfaffl, Bettina Haase, Chun‐Xia Yi, Sarah Dietzen, Tobias Bopp, Stephen C. Woods, Ari Waisman, Benno Weigmann, Matthias Mann, Matthias Tschoep, Carolin Daniel
Abstract
Abstract The hypothalamus in the central nervous system (CNS) has important functions in controlling systemic metabolism. A calorie-rich diet triggers CNS immune activation, impairing metabolic control and promoting obesity and Type 2 Diabetes (T2D), but the mechanisms driving hypothalamic immune activation remain unclear. Here we identify regulatory T cells (Tregs) as key modulators of hypothalamic immune responses. In mice, calorie-rich environments activate hypothalamic CD4 + T cells, infiltrating macrophages and microglia while reducing hypothalamic Tregs. mRNA profiling of hypothalamic CD4 + T cells reveals a Th1-like activation state, with increased Tbx21 , Cxcr3 and Cd226 but decreased Ccr7 and S1pr1 . Importantly, results from Treg loss-of function and gain-of-function experiments show that Tregs limit hypothalamic immune activation and reverse metabolic impairments induced by hyper-caloric feeding. Our findings thus help refine the current model of Treg-centered immune-metabolic crosstalk in the brain and may contribute to the development of precision immune modulation for obesity and diabetes.