Spatial transcriptomics from pancreas and local draining lymph node tissue reveals a lymphotoxin-β signature in human type 1 diabetes

This study explores the inflammatory response observed in the pancreas and pancreatic lymph nodes (pLNs) during the natural history of type 1 diabetes (T1D). Using multicell-resolution spatial transcriptomics (ST), we profile individuals without diabetes (ND), at-risk autoantibody-positive (AAb+) individuals, and T1D donors. In the T1D pancreas, we observed global upregulation of inflammation-associated transcripts, including REG family genes, C3, SOD2, and OLFM4. In the T1D pLN, LTB was significantly upregulated within the lymphoid follicles. Using an orthogonal subcellular-resolution ST platform on an independent donor set, we identified follicular B cells as the primary source of LTB in the pLN and observed increased LTB expression in lymphocytes in insulitic lesions proximal to CCL19/CCL21-expressing endothelium. Collectively, these findings highlight lymphotoxin-β and downstream chemokine signatures in the pancreatic lymphatics as well as within the insulitic lesion, which can inform future therapeutic interventions.