Cytocidal Macrophages Cause Acute Diabetes following Checkpoint Blockade of PD-1 in NOD Mice

Blocking the action of the PD-1 protein in lymphocytes results in their activation leading to an effective immune response in cancers and in experimental viral infections. But such immunotherapy in clinical cases results in immune adverse effects among them the development of autoimmune diabetes. In the diabetes susceptible NOD mice, blockade of the PD-L1/PD-1 pathway during the pre-diabetic stage results in severe and acute diabetes. Single-cell RNA sequencing and flow cytometry analysis of islets following blockade of the PD-L1/PD-1 pathway identified a cascade of cellular interactions involving resident macrophages and diabetogenic T cells. Such reactions led to the recruitment of monocyte derived macrophages that caused diabetes. Elimination of the monocyte derived macrophages resulted in protection. The cytocidal activity was highly dependent on IFN? signaling and the downstream release of nitric oxide by the monocyte derived macrophages. The activation of macrophages required both the participation of CD4 and CD8 T cells. Our studies call attention to macrophages as the major effector cell following blockade of PD-1. Targeting the monocyte-derived macrophage provides a new option to prevent and treat immune checkpoint blockade induced diabetes and perhaps other immune adverse reactions. Overall design: 10X Single-cell RNASeq