Shaping diabetogenic T cells by IL-27 in type 1 diabetes

Type 1 diabetes (T1D) is a life-long disease requiring daily injections of exogenous insulin. The incidence of T1D has been increasing worldwide in recent decades. Improved understanding of the cellular and molecular mechanisms that account for the diabetogenesis will be greatly helpful in therapeutic designs to treat or delay the onset of T1D. Although both CD4 and CD8 T cells are required for T1D development, how β-cell autoreactive T cells are activated, accumulate, and maintain their effector function during T1D progression has not been fully defined. In this application, we aim to determine the mechanisms by which an important inflammatory cytokine IL-27 impacts T1D through its direct effects on both CD4 and CD8 T cells. In this study, my research team will assist Dr. Chen to characterize the autoreactive CD4 helper cells and CD8 effector cells through a high-throughput and high-dimensionality approach that has been recently established in my laboratory. This approach combines single-cell RNA sequencing (scRNA-seq) with single-cell TCR sequencing (scTCR-seq), which allows us to study the function, differentiation trajectory and TCR diversity of β-cell reactive T cells all at once. This not only helps to overcome the difficulties in studying a very small number of immune cells in islets by using traditional methods such as flow cytometry but also provides unprecedented opportunities to discover new subsets of T cells that might be more specific in diabetogenesis.