Phenotypic alterations in pancreatic lymph node stromal cells from human donors with type 1 diabetes and NOD mice

Abstract

Aims/hypothesis Tolerance induction in lymph nodes can be mediated by both haematopoietic cells (e.g. specific dendritic cells subsets) and by non-haematopoietic cells (e.g. lymph node stromal cells [LNSCs]) when they present peripheral tissue antigens to autoreactive T cells. LNSCs normally regulate T cell trafficking and survival and help to maintain peripheral tolerance by exerting immunosuppressive effects. However, whether autoimmunity can be associated with defective tolerogenic functions of LNSCs is unknown and studies aimed at characterising LNSCs in humans are lacking. We hypothesised that dysregulated T cell responses in pancreatic lymph nodes (PLNs) from donors with type 1 diabetes and from NOD mice may be associated with altered LNSC function. Methods We analysed PLNs from donors with type 1 diabetes and NOD mice for LNSC distribution and phenotype using flow cytometry. We assessed the expression of tolerance-related genes in different subsets of LNSCs from human donors, as well as in a population of dendritic cells enriched in autoimmune regulator (AIRE) + cells and identified as HLA-DR high CD45 low. Results The relative frequency of different LNSC subsets was altered in both donors with type 1 diabetes and NOD mice, and both MHC class II and programmed death-ligand 1 (PD-L1) expression were upregulated in human type 1 diabetes. Tolerancerelated genes showed similar expression profiles between mouse and human LNSCs at steady state but were generally upregulated in the context of human type 1 diabetes, while, at the same time, many such genes were downregulated in the AIREenriched dendritic cell population. Conclusion/interpretation Our study shows that LNSCs are substantially altered in type 1 diabetes, but, surprisingly, they exhibit an enhanced tolerogenic phenotype along with increased antigen-presenting potential, which may indicate an attempt to offset dendritic cell-related tolerogenic defects in tolerance. Thus, LNSCs could constitute alternative therapeutic targets in which to deliver antigens to help re-establish tolerance and prevent or treat type 1 diabetes. Data availability All data generated or analysed during this study are included in the published article (and its online supplementary files). Biomark gene expression data were deposited on the Mendeley repository at https://data.mendeley.com/datasets/ d9rdzdmvyf/1. Any other raw datasets are available from the corresponding author on reasonable request. No applicable resources were generated or analysed during the current study.

Human Lymph Node Stromal Cells Have the Machinery to Regulate Peripheral Tolerance during Health and Rheumatoid Arthritis

“…Next to possible antigen presentation by LNSCs, we demonstrated in this study that human LNSCs possess an arsenal of immunomodulatory molecules both in vitro on cultured human LNSCs and ex vivo on freshly isolated human LNSCs. As previously reported, PD-L1 expression is mostly restricted to endothelial cells (LECs and BECs) on freshly isolated human LN [59]. Similarly, our data also showed that PD-L1 protein expression was higher on endothelial cells in comparison to FRCs and DNs.…”

LN-Derived Fibroblastic Reticular Cells and Their Impact on T Cell Response—A Systematic Review

“…Consequently, FRCs modulated their interactions with autoreactive T lymphocytes by remodeling their reticular network in LNs; PTAs and podoplanin played a central role and their alterations may favor T1D [ 21 ]. These findings are supported by a previous study from the same group that investigated alterations in pancreatic lymph nodes from humans and mice [ 52 ]. Kasinath et al studied crescentic glomerulonephritis (GN), an autoimmune inflammatory condition characterized by the rapid deterioration of kidney function.…”

Nanoparticles versus Dendritic Cells as Vehicles to Deliver mRNA Encoding Multiple Epitopes for Immunotherapy

“…More importantly, we recently reported that stromal cells in the PLNs of T1D patients (the same lymph nodes as those targeted by mRNA-NPs after i.p. in mice) had higher antigen presentation and tolerogenic potential than those in control individuals 55 . Thus, the ability to target antigens to LNSCs with mRNA-NPs as shown here is therapeutically relevant.…”