Editors' ChoiceImmunology

Enhancing cytotoxic T cells by inhibiting GSK3

Sci. Signal.  15 Mar 2016:
Vol. 9, Issue 419, pp. ec58
DOI: 10.1126/scisignal.aaf6700

In response to chronic viral infections, CD8+ cytotoxic T cells become exhausted, a state that is characterized by an increase in the cell-surface abundance of the coreceptor PD-1 and a decrease in cytolytic function. PD-1 signaling is also subverted in the tumor microenvironment to suppress the antitumor activity of CD8+ T cells. Taylor et al. found that knockdown or inhibition of glycogen synthase kinase 3 (GSK3) in mouse CD8+ T cells reduced the cell surface abundance of PD-1 and enhanced the cytolytic response against a mouse lymphoma cell line. Knockdown or inhibition of GSK3 reduced the expression of the gene encoding PD-1 (Pdcd1) in T cell receptor (TCR)–stimulated CD8+ T cells compared with that in control TCR-stimulated cells, whereas expression of the gene encoding the transcriptional regulator T-bet was increased. Chromatin immunoprecipitation analysis of TCR-stimulated CD8+ T cells showed that GSK3 inhibition increased the amount of T-bet that associated with the Pdcd1 promoter. Knockdown of T-bet in GSK3-inhibited CD8+ T cells resulted in increased PD-1 abundance on the cell surface and decreased cytolytic activity. TCR transgenic mice injected with antigenic peptide in the presence of a GSK3 inhibitor generated CD8+ T cells that were more cytolytic than those from similarly treated mice that were not given the inhibitor. Last, in two mouse models of viral infection, small-molecule inhibitors of GSK3 reversed CD8+ T cell exhaustion, which was associated with decreased PD-1 abundance, and enhanced cytolytic function and viral clearance. Together, these data indicate that inhibition of GSK3 reduces the cell-surface abundance of PD-1 on CD8+ T cells to enhance their cytotoxic function, which suggests that GSK3 inhibitors, which are used clinically to treat neurological disorders, may be repurposed to treat cancer or viral infection.

A. Taylor, J. A. Harker, K. Chanthong, P. G. Stevenson, E. I. Zuniga, C. E. Rudd, Glycogen synthase kinase 3 inactivation drives T-bet-mediated downregulation of co-receptor PD-1 to enhance CD8+ cytolytic T cell responses. Immunity 44, 274–286 (2016). [PubMed]