Spatial transcriptomics from paired pancreas and associated draining lymph nodes reveals a lymphotoxin-beta signature in human type 1 diabetes

This study explores the inflammatory response involved in type 1 diabetes (T1D) using multi-cell resolution spatial transcriptomics (ST) to assay paired pancreas and pancreatic lymph node (pLN) samples from human donors across the natural history of T1D. Integration of ST with public single-cell RNA sequencing data enabled interrogation of transcriptional alterations in T1D across both tissues at the cellular scale. In the T1D pancreas, we identified global upregulation of inflammation-associated transcripts, including multiple regenerating islet-derived (REG) family genes, complement factor 3 (C3), SOD2, and OLFM4, and highlighted cellular candidates potentially contributing to these signatures. Within the T1D pLN, we observed spatially restricted upregulation of lymphotoxin- (LTB) alongside follicular dendritic cell (FDC)-associated transcripts including FDCSP, CLU, and FCER2. Collectively, these findings highlight a distinct inflammation signature in the pancreas and evidence of enhanced follicular activity in the associated pLN. Spatial transcriptomics using the 10x Genomics Visium spatial gene expression assay performed on human donor pancreas and associated pancreatic lymph node sections from non-diabeitc controls, non-diabetic islet autoantibody positive donors at high risk, and T1D donors.

本研究借助多细胞分辨率空间转录组学（spatial transcriptomics, ST），探究参与1型糖尿病（type 1 diabetes, T1D）的炎症反应，对覆盖T1D自然病程全过程的人类供体配对胰腺与胰腺淋巴结（pLN）样本开展检测。将空间转录组学数据与公开的单细胞RNA测序数据整合后，得以在细胞尺度下解析两种组织内T1D相关的转录组改变。在T1D患者的胰腺组织中，本研究鉴定出炎症相关转录本的整体上调，包括多个再生胰岛衍生（REG）家族基因、补体因子3（C3）、超氧化物歧化酶2（SOD2）及嗅素4（OLFM4），并明确了可能促成这些分子特征的候选细胞群。在T1D患者的pLN中，我们观察到淋巴毒素β（LTB）的空间限制性上调，同时伴随滤泡树突状细胞（FDC）相关转录本（如滤泡树突状细胞分泌蛋白（FDCSP）、簇蛋白（CLU）及FCER2）的表达升高。综上，本研究揭示了胰腺组织中独特的炎症特征，以及相关pLN中滤泡活性增强的证据。本研究采用10x Genomics Visium空间基因表达检测技术，对三类供体的胰腺及配套胰腺淋巴结组织切片进行分析：非糖尿病对照组供体、非糖尿病胰岛自身抗体阳性的高风险供体，以及T1D患者供体。