ESPE Yearbook of Paediatric Endocrinology

Nat Commun. 2025;16(1):4621. PMID: 40383826

Brief summary: This comprehensive study analysed immune cells from pancreatic, mesenteric, and splenic lymphatic tissues of autoantibody-negative individuals without T1D (ND), autoantibody-positive individuals (AAb+), and donors with type 1 diabetes (T1D). Decreased naïve T cells and increased cytotoxic NK cells were observed in the peripheral lymph nodes (pLNs) of individuals with T1D, along with a marked reduction in CD25 expression on both CD4⁺ and CD8⁺ T cells. Additionally, decreased CD4⁺ regulatory T cells (Tregs) were detected in the pLNs of antibody-positive individuals, even before T1D onset.

Autoimmune destruction of pancreatic β cells results in T1D, and evidence suggests that pancreatic lymph nodes (pLN) harbor immune cells that participate in this process (1). However, the immunological mechanisms occurring within human pancreas-draining lymphoid tissues remain poorly understood.

In this study, lymphoid immune perturbations were profiled in pLNs, mesenteric lymph nodes (mLNs), and spleens from a cross-sectional cohort of ND, AAb+, and T1D individuals. Deep immunophenotyping was performed using high-parameter flow cytometry (n= 46 donors) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq; n= 18 donors). In AAb⁺ and T1D donor pLNs, a reduced frequency and increased instability of CD4⁺ regulatory T cells (Tregs) were observed compared to ND pLNs, while memory CD8⁺ T cells showed more pronounced stem-like characteristics. Increased differentiation of naïve T cells and NK cells was detected only in pLNs from T1D donors. In mLNs, alterations were limited to CD4⁺ Tregs and naïve T cells, whereas few perturbations were noted in splenocytes.

Overall, the study identified significant immune perturbations occurring primarily within pLNs, both before and after the onset of T1D. In contrast, these changes were less pronounced in mLNs and absent in splenocytes. These findings emphasize the importance of pLNs as a key site for immune cell interactions and a potential future target for immunotherapies.

Reference: 1. Sun F, Yang CL, Wang FX, et al. Pancreatic draining lymph nodes (PLNs) serve as a pathogenic hub contributing to the development of type 1 diabetes. Cell Biosci 2023;13(1):156.