ICOS signaling limits regulatory T cell accumulation and function in visceral adipose tissue

Abstract

A unique population of Foxp3+ regulatory T cells (TR) resides in visceral adipose tissue (VAT) that regulates adipose inflammation and helps preserve insulin sensitivity. The costimulatory molecule ICOS is highly expressed on effector (e)TR that migrate to nonlymphoid tissues, and contributes to their maintenance and function in models of autoimmunity. In this study, we report an unexpected cell-intrinsic role for ICOS expression and downstream PI3K signaling in limiting the abundance, VAT-associated phenotype, and function of TR specifically in VAT. Icos-/- mice and mice expressing a knock-in form of ICOS that cannot activate PI3K had increased VAT-TR abundance and elevated expression of canonical VAT-TR markers. Loss of ICOS signaling facilitated enhanced accumulation of TR to VAT associated with elevated CCR3 expression, and resulted in reduced adipose inflammation and heightened insulin sensitivity in the context of high-fat diet. Thus, we have uncovered a new and surprising molecular pathway that regulates VAT-TR accumulation and function. SummaryThe authors demonstrate that loss of ICOS-dependent PI3-kinase signaling supports visceral adipose tissue (VAT) TR abundance and function, and this correlates with reduced adipose inflammation and improved insulin sensitivity after high-fat diet. This work highlights a new molecular pathway that regulates VAT-TR accumulation and activity.