Homeostatic PD-1 signalling restrains Eomes-dependent oligoclonal expansion of liver- resident CD8 T cells [scRNA-seq]

The coinhibitory PD-1 signalling pathway plays a major role in the context of tumor-specific T cell responses. Conversely, it also contributes to the maintenance of peripheral tolerance as patients receiving anti-PD-1 treatment are prone to developing immune-related adverse events. Yet, the physiological role of the PD-1/PDL-1 axis in T cell homeostasis is still poorly understood. Herein, we show that under steady-state conditions, the absence of PD-1 signaling led to a preferential expansion of CD8+ T cells in the liver. These cells exhibited an oligoclonal TCR repertoire and a terminally differentiated exhaustion profile with high levels of the transcription factors TOX and EOMES. Using loss- or gain-of-function strategies, we could demonstrate that EOMES was required for the clonal expansion and acquisition of this differentiation program. Furthermore, single cell transcriptomics coupled to TCR repertoire analysis strongly supported the notion that these cells arise locally from liver-resident memory CD8 T cells. With these results, we uncovered an unexpected role for PD-1 signaling in liver memory T cell homeostasis. Overall design: Using gain-of-function strategie, we developed mice expressing Eomes in T cells to study its role in the acquisition of a specific transcriptional program and clonal expansion of CD8+ T cells in spleen and liver.