Single-cell profiling reveals unique features of diabetogenic T cells in anti-PD-1-induced type 1 diabetes mice

Collier et al. identify unique features of diabetogenic T cells in the pancreas and peripheral tissues between anti-PD-1-induced type 1 diabetes (T1D) and spontaneous T1D in non-obese diabetic mice and provide a rationale for monitoring immune-related adverse events in the blood. Immune-related adverse events (irAEs) are a notable complication of PD-1 cancer immunotherapy. A better understanding of how these iatrogenic diseases compare with naturally arising autoimmune diseases is needed for treatment and monitoring of irAEs. We identified differences in anti-PD-1-induced type 1 diabetes (T1D) and spontaneous T1D in non-obese diabetic (NOD) mice by performing single-cell RNA-seq and TCR-seq on T cells from the pancreas, pancreas-draining lymph node (pLN), and blood of mice with PD-1-induced T1D or spontaneous T1D. In the pancreas, anti-PD-1 resulted in expansion of terminally exhausted/effector-like CD8(+) T cells, an increase in T-bet(hi) CD4(+)FoxP3(-) T cells, and a decrease in memory CD4(+)FoxP3(-) and CD8(+) T cells in contrast to spontaneous T1D. Notably, anti-PD-1 caused increased TCR sharing between the pancreas and the periphery. Moreover, T cells in the blood of anti-PD-1-treated mice expressed markers that differed from spontaneous T1D, suggesting that the blood may provide a window to monitor irAEs rather than relying exclusively on the autoimmune target organ.