Exhausted CD8 T cells exhibit strongly inhibited TCR signaling during chronic infection
Chronic infections are characterized by the inability of CD8 T cells to clear the virus leading to persistent viral loads. A recent ‘Nature Communications’ paper by the Oxenius (IMB) and Claassen groups (IMSB) shows that CD8 T cells are strongly inhibited in vivo, but retain cytotoxic potential.
Chronic viral infections are often associated with impaired CD8 T cell function, known as exhaustion. The molecular and cellular circuits involved in CD8 T cell exhaustion have been well studied and revealed the importance of sustained antigen presence and expression of immune checkpoint inhibitors. The Oxenius and Claassen groups characterized the in vivo T cell receptor signaling of exhausted CD8 T cells in a mouse model, leveraging T cell receptor (TCR) signaling reporter mice in combination with transcriptomics. These data show 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 checkpoint blockade and adoptive transfer of target cells not expressing checkpoint inhibitors increase T cell receptor signaling, demonstrating that engagement of checkpoint inhibitors profoundly curtails CD8 T cell signaling and function in vivo.
The engagement of a CD8 T cell with an infected target cell via the T cell receptor leads to the activation of the transcription factor NUR77. An important feature of exhausted CD8 T cells is the co-expression of multiple co-inhibitory receptors such as PD-1, which dampen T cell activation as measured by NUR77 expression (I). Absence of inhibitory ligands (such as PD-L1) on target cells (II) or checkpoint blockade (III) lead to increased signaling in exhausted virus-specific CD8 T cells in vivo.
Link to the paper in external page "Nature Communications".