Graduate Student Harvard University Boston, Massachusetts, United States
Disclosure(s):
Sarah Lane-Reticker: No financial relationships to disclose
Introduction/Rationale: Autoimmune diabetes occurs when T cells destroy the insulin-producing beta cells of the pancreatic islets, but antigen-presenting cells (APCs) are required to initiate this cascade. T-cell autoreactivity is thought to begin following a developmental wave of islet cell death that occurs during weaning in both healthy and autoimmune individuals; this wave of cell death releases islet antigens. Concurrently during the weaning period, immune tolerance is being established across the body, and specialized APCs arise that are able to shape lifelong T-cell responses. Do islet APCs also help promote tolerance to islet antigen during the wave of developmental cell death?
Methods: We used single-cell RNAseq to profile islet APCs before, during, and after the wave of cell death in islet-tolerant and islet-autoreactive mouse strains.
Results: We found that initial insulin antigen release coincides with the expansion of islet-resident macrophages and is mediated by similar subsets of macrophages and dendritic cells in both tolerance and autoimmunity. However, we found strain differences in how APCs respond to insulin antigen release. These differences encompassed insulin antigen presentation as well as genes associated with cell trafficking and immune suppression that could contribute to the initiation of autoimmunity. Importantly, these differences preceded programs driven by T cell-mediated inflammation.
Conclusion: We characterized a conserved APC response to the early life wave of beta cell death and antigen release and have identified macrophage and dendritic cell phenotypes that may contribute to disease initiation in the NOD mouse model.
