T cell receptor signaling in exhausted virus-specific CD8 T cells is low and strongly inhibited in vivo during chronic LCMV infection. TCR signaling RNAseq

Chronic viral infections are often associated with impaired CD8 T cell function, referred to as exhaustion. While the molecular and cellular circuits involved in CD8 T cell exhaustion have been well defined, with sustained presence of antigen being one important parameter, it remains unclear how much T cell receptor (TCR) signaling is actually ongoing in vivo during established chronic infection. In this study, we characterized the in vivo TCR signaling of virus-specific exhausted CD8 T cells in a mouse model, by taking advantage of Nr4a1-GFP reporter mice and bulk RNAseq. We found that the in vivo signaling in exhausted cells is low, in contrast to their in vitro signaling potential, and despite antigen being abundantly present. Both α-PD-L1 blockade and adoptive transfer of naïve target cells increased TCR signaling in vivo, demonstrating that engagement of co-inhibitory receptors, such as PD-1, profoundly curtails TCR signaling in vivo.