Evidence of islet CADM1-mediated immune cell interactions during human type 1 diabetes.

ABSTRACT

BACKGROUNDPathophysiology of type 1 diabetes (T1D) is illustrated by pancreatic islet infiltration of inflammatory lymphocytes, including CD8+ T cells; however, the molecular factors mediating their recruitment remain unknown. We hypothesized that single-cell RNA-sequencing (scRNA-Seq) analysis of immune cell populations isolated from islets of NOD mice captured gene expression dynamics providing critical insight into autoimmune diabetes pathogenesis.METHODSPancreatic sections from human donors were investigated, including individuals with T1D, autoantibody-positive (aAb+) individuals, and individuals without diabetes who served as controls. IHC was performed to assess islet hormones and both novel and canonical immune cell markers that were identified from unbiased, state-of-the-art workflows after reanalyzing murine scRNA-Seq data sets.RESULTSComputational workflows identified cell adhesion molecule 1-mediated (Cadm1-mediated) homotypic binding among the most important intercellular interactions among all cell clusters, as well as Cadm1 enrichment in macrophages and DCs from pancreata of NOD mice. Immunostaining of human pancreata revealed an increased number of CADM1+glucagon+ cells adjacent to CD8+ T cells in sections from T1D and aAb+ donors compared with individuals without diabetes. Numbers of CADM1+CD68+ peri-islet myeloid cells adjacent to CD8+ T cells were also increased in pancreatic sections from both T1D and aAb+ donors compared with individuals without diabetes.CONCLUSIONIncreased detection of CADM1+ cells adjacent to CD8+ T cells in pancreatic sections of individuals with T1D and those who were aAb+ validated workflows and indicated CADM1-mediated intercellular contact may facilitate islet infiltration of cytotoxic T lymphocytes and serve as a potential therapeutic target for preventing T1D pathogenesis.FUNDINGThe Johns Hopkins All Children's Foundation Institutional Research Grant Program, the National Natural Science Foundation of China (grant 82071326), and the Deutsche Forschungsgemeinschaft (grants 431549029-SFB1451, EXC2030-390661388, and 411422114-GRK2550).