Type 1 diabetes (T1D) is characterized by the hyperglycemia resulting from the autoimmune destruction of the insulin–expressing β–cells of the pancreas. As the prevalence of the disease continues to increase worldwide, it remains imperative to identify therapeutic strategies that can (1) preserve pancreatic beta–cell mass and function and (2) prevent the immune response that initiates the pathogenesis of T1D. Cell adhesion molecule 1 (referred to as human CADM1 and mouse Cadm1, and also known as SynCAM1, TSLC1, and Necl2) is an immunoglobulin–domain–containing membrane protein shown to mediate homo–and heterophilic cell–to–cell contact with other CADM family members. It has also been shown that CADM1+ cells will bind CD8+ T–cells via the receptor Class 1–restricted T–Cell–associated Molecule (CRTAM) present in the immune cells; and we recently showed the number of CADM1–expressing myeloid cells are increased within the human pancreatic islet during human T1D. These results suggest CADM1–expressing populations may contribute to the recruitment and activation of CD8+ T cells that leads to destruction of beta–cells. Preliminary results show CADM1-expressing myeloid cells in islets of NOD mice are also enriched for expression of Toll–like receptor 7 (TLR7) and DC–SIGN, two established activators of innate immune cell populations shown to bind a broad range of pathogens. The goal of this work is to perform (1) multiplex immunohistochemical analysis to quantify CADM1+ myeloid cells that express TLR7 and DC–SIGN within islets of auto–antibody positive and T1D subjects and (2) spatial transcriptomic analysis to identify additional co–factors of CADM1–expressing cells during T1D. This work seeks to establish that increased numbers of CADM1–expressing myeloid cells are in proximity to CD8+ T cells in islets of aAb+ and T1D human subjects. Completion of the proposed studies may establish CADM1+TLR7+DC–SIGN+ cells as potential therapeutic targets for preserving beta cell mass and function and for attenuating the inflammatory response during the pathogenesis of T1D.
