Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset

Autoimmune destruction of pancreatic β cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. Studies of human T1D immunobiology have predominantly focused on circulating immune cells in the blood, while mouse models suggest diabetogenic lymphocytes primarily reside in pancreas-draining lymph nodes (pLN). A comprehensive study of immune cells in human T1D was conducted using pancreas draining lymphatic tissues, including pLN and mesenteric lymph nodes (mLN), and the spleen from non-diabetic control, β cell autoantibody positive non-diabetic (AAb+), and T1D organ donors using complementary approaches of high parameter flow cytometry and CITEseq. Immune perturbations suggestive of a proinflammatory environment were specific for T1D pLN and AAb+ pLN. Compared to ND, AAb+ and T1D pLN have a reduced Treg signature and increased stem-like CXCR3 + GZMK - TOX -CD8+ T cells. Several perturbations in the pLN were T1D specific, including a reduced naive T cell signature and an increased frequency of cytotoxic CD56dimCD16+ NK cells. Some, but not all, immune changes were found in the mLN and spleen. In addition, certain immune populations correlated with high T1D genetic risk independent of disease state. These datasets form an extensive resource for profiling human lymphatic tissue immune cells in the context of autoimmunity and T1D.