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

Tolerance induction in lymph nodes can be mediated by both hematopoietic cells, such as AIRE-expressing dendritic cells (DCs), and non-hematopoietic cells, such as 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 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 characterizing LNSCs in humans are lacking. We hypothesized that dysregulated T cell responses in pancreatic lymph nodes (PLNs) from patients and mice with Type 1 diabetes may be associated with altered LNSC function. We analyzed PLNs from Type 1 diabetes patients for expression of tolerance-related genes in different subsets of LNSCs (as well as AIRE-expressing DCs) from human donors. Tolerance-related genes in human LNSCs showed similar expression profiles to those of mouse LNSCs (ImmGen.org) at steady state, but tended to be upregulated in the context of Type 1 diabetes, while at the same time, many such genes were downregulated in the DC population comprising AIRE+ cells. Our study shows that LNSCs are substantially altered in Type 1 diabetes, but they surprisingly exhibit an enhanced tolerogenic phenotype, which may indicate an attempt to offset DC-related tolerogenic defects in tolerance.