Abstract
SummaryDespite the importance of the co-receptor PD-1 in T cell immunity, the upstream signaling pathway that regulates PD-1 expression has not been defined. Glycogen synthase kinase 3 (GSK-3, isoforms α and β) is a serine-threonine kinase implicated in cellular processes. Here, we identified GSK-3 as a key upstream kinase that regulated PD-1 expression in CD8+ T cells. GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8+ cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8+ CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8+ OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy.
Highlights
Persistent viral infections are often associated with the functional exhaustion of virus-specific CD8+ T cells (Virgin et al, 2009)
Receptor programmed death 1 (PD-1; known as PDCD1) expression is upregulated on the surface of exhausted CD8+ T cells in mice infected by the lymphocytic choriomeningitis virus clone 13 strain (LCMV-Cl13) (Barber et al, 2006; Day et al, 2006; Freeman et al, 2006; Sharpe et al, 2007)
We initially examined cytotoxic T lymphocyte (CTL) responses of T cells from OT-I transgenic mice that carry a MHC class I-restricted T cell receptor (TCR) specific for the SIINFEKL peptide of OVAlbumin (OVA257-264) as presented by H-2kb
Summary
Persistent viral infections are often associated with the functional exhaustion of virus-specific CD8+ T cells (Virgin et al, 2009). Receptor programmed death 1 (PD-1; known as PDCD1) expression is upregulated on the surface of exhausted CD8+ T cells in mice infected by the lymphocytic choriomeningitis virus clone 13 strain (LCMV-Cl13) (Barber et al, 2006; Day et al, 2006; Freeman et al, 2006; Sharpe et al, 2007). Blocking antibodies against PD-1 restores CD8+ T cell functionality and viral clearance (Freeman et al, 2006; Ha et al, 2008; Sharpe et al, 2007; Wherry, 2011). Checkpoint inhibitor blockade has proven effective in the treatment of cancers such as melanoma (Hodi et al, 2003, 2010) and in combined therapy with anti-CTLA-4 (Topalian et al, 2015; Wolchok et al, 2013)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
