PD-1 localization in the immunological synapse is different in exhausted as compared to effector LCMV specific CD8 T cells (90.12)

Abstract

Abstract Understanding the molecular basis of ineffective T cell response during chronic viral infections may provide new therapeutic targets. Our studies in lymphocytic choriomeningitis virus (LCMV) infection provided the first indication that programmed death-1 (PD-1) pathway regulate T cell dysfunction during chronic infection. These findings were extended to HIV, SIV, HBV and HCV infections and suggest that in vivo blockade of PD-1 pathway may provide a therapeutic approach for human chronic infections. However, further studies are needed to determine how best to modulate PD-1 signaling to activate anti-viral T cells while minimizing immunopathology. Understanding these signaling effects would be greatly advanced by direct imaging of PD-1 in relation to signaling structures in the immunological synapse. Using LCMV model, we investigated PD-1 localization at the T:DC synapse by direct imaging of PD-1 in relation to T cell receptor by confocal microscopy. We compared P14 (LCMV gp33-specific) effector and exhausted cells from mice infected with LCMV Armstrong and clone 13 strains, respectively. Here we show that PD-1:TCR co-localization at the T:DC synapse is different between exhausted and effector CD8 T cells. Our study provides important informations on molecular mechanisms behind T cell exhaustion and may help to identify novel targets to modify PD-1 signaling for the treatment of human chronic infections.