Dynamic remodeling of the pancreas immune landscape in obesity

Obesity is a known risk factor for diseases of the pancreas, including diabetes, pancreatic cancer and pancreatitis, but mechanisms remain unclear. Here we show by spatial, transcriptomic and functional profiling of human pancreatic immune cells from obese and non-obese organ donors that obesity profoundly impacts pancreatic immune homeostasis. Obesity is associated with higher density of tissue resident memory T-cells (TRM) in the exocrine pancreas which are characterized by high cytotoxic functions, and aggregate around macrophages. Single cell sequencing of pancreatic macrophages distinguishes two main subsets - FOLR2 + CD11c- foetal-derived macrophages with pro-repair and immunoregulatory function and FOLR2- CD11c+ lipid-associated macrophages with greater T-cell interactions and pro-inflammatory function. In obesity, the pancreatic macrophage landscape shifts to lower predominance of FOLR2 + CD11c- macrophages and expansion of FOLR2- CD11c+ macrophages, which interact selectively with the TRM and inflamed exocrine epithelium. Together, these results identify macrophage-T cell circuits and immune epithelial interactions that might lead to chronic pancreatic inflammation in obesity and might contribute to obesity-related pancreatic diseases.