PD-1 Is Involved in the Dysregulation of Type 2 Innate Lymphoid Cells in a Murine Model of Obesity

Abstract

Summary: Recent observations clearly highlight the critical role of type 2 innate lymphoid cells in maintaining the homeostasis of adipose tissues in humans and mice. This cell population promotes beiging and limits adiposity directly and indirectly by sustaining a Th2-prone environment enriched in eosinophils and alternatively activated macrophages. Accordingly, the number and function of type 2 innate lymphoid cells (ILC2s) are strongly impaired in obese individuals. In this work, we identify the PD-1-PD-L1 pathway as a factor leading to ILC2 destabilization upon high-fat feeding resulting in impaired tissue metabolism. Tumor necrosis factor (TNF) appears to play a central role, triggering interleukin-33 (IL-33)-dependent PD-1 expression on ILC2s and recruiting and activating PD-L1hi M1 macrophages. PD-1 blockade partially restores the type 2 innate axis, raising the possibility of restoring tissue homeostasis. : The function of ILC2s is compromised during obesity. Here, Oldenhove et al. show that ILC2 inhibition is mediated by the PD-1-PD-L1 pathway. PD-1 blockade in obese mice improved ILC2 function, reinforced type 2 innate responses, and promoted tissue homeostasis. PD-1 may therefore represent a target for immune intervention in obesity-associated disorders. Keywords: obesity, adipose tissue, innate lymphoid cells, ILC2, macrophage, PD-1, PD-L1, TNF, IL-33