Ad - hoc Dr. Alison Taylor: Glycogen synthase kinase 3 regulates PD-1 expression for enhanced CD8+ cytolytic T-cell responses

Cell Signalling Section, Department of Pathology, Tennis Court Road, University of Cambridge, UK;

Programmed death (PD)-1 is a co-receptor on T-cells that negatively modulates T-cell responses.  PD-1 up-regulation is responsible for the exhaustion of virus-specific CD8 T-cell responses to Hepatitis C, human immunodeficiency virus 1 (HIV-1) and others. Further, reagents that block the PD-1/B7-H1 interaction can restore effector CD8+ T cell responses in chronic viral infection and provide anti-tumor protection. A key question now concerns the identity of the signalling pathway that regulates PD-1 and the regulation of anti-viral immunity.  Here, we show a signalling pathway in which the serine/threonine kinase - glycogen synthase kinase-3 (GSK-3) regulates PD-1 and that GSK-3α/β inactivation by siRNA or small molecular inhibitors selectively blocked PD-1 expression, without affecting other receptors, and enhanced cytolytic T cell function. GSK-3α/β operated by enhancing T-bet (Tbx21) transcription and in turn repressed PD-1. This inhibition of PD-1 enhanced in vivo clearance of acute and chronic infections by Murid herpes virus-4 (MHV-68) and lymphocytic choriomeningitis-Cl 13 (LCMV-Cl 13). We also showed in vivo that inactivation of GSK-3 down-regulates PD-1 expression correlating with enhanced cytolytic T-cell killing of tumour cells preventing tumour growth. PDL-1 blocking reagents mimicked these responses and when combined, this therapy is even more effective.  Together, these findings identify GSK-3α/β as a key central regulator of PD-1 transcription and offer the possibility of a novel therapeutic approach in the reversal of defective immune responses to chronic viral infection and possibly cancer.  

The host for this seminar is