An interleukin-27 centered cytokine circuit regulates macrophage and T cell interactions in autoimmune diabetes

In the NOD mouse model of autoimmune diabetes, IL-27 stimulates CD4 and CD8 T cells to enhance their IFN? production and diabetogenic capacity. Here, single-cell RNA sequencing and T cell adoptive transfer showed that IL-27 intrinsically controlled the differentiation of islet-infiltrating CD4 T cells by driving them toward an IL-21+ Th1 phenotype. Consequently, IL-27 signaling in CD4 T cells was important for BATF and granzyme B expression in islet CD8 T effectors. Complete absence of IL-21 signaling in CD8 T cells additionally impaired their cytokine production. BATF overexpression increased the diabetogenic potential of ß-cell autoreactive CD8 T cells lacking help from CD4 T cell-derived IL-21. Macrophages were the main source of IL-27 in islets, whose expression correlated with T cell infiltration. IFN? and CD40 signaling conferred by activated T cells induced macrophage IL-27 production. Collectively, our findings reveal a role of IL-27 in orchestrating interconnected positive feedback loops involving CD4 T cells, CD8 T cells, and macrophages in autoimmune diabetes. Overall design: Islet-infiltrating T cells from mixed bone marrow chimera mice were isolated by fluorescence-activated cell sorting (FACS) according to the presence of CD45.1 or CD45.2 expression and analyzed by scRNA-seq.