Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8+ Cytolytic T Cell Responses

Alison Taylor,James A. Harker,Kittiphat Chanthong,Philip G. Stevenson,Elina I. Zuniga,and Christopher E. Rudd

(Immunity 2016; 44, 274–286)

Speaker：Yu-ling Chen (陳又菱)                                        Time：15:10~16:00, Jun. 8, 2016

Commentator：Dr. Bei-Chang Yang (楊倍昌 教授)          Place：Room 601

Abstract：

There are many receptors associated with T cell immunity. As we know, programmed cell death 1 (PD-1) is an inhibitory receptor expressed on activated T cells.¹ Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, which modulates immune responses of T cells. Whether GSK-3 regulates PD-1 transcription and expression in T cells remains unknown. Inactivation of GSK-3 downregulates the expression of PD-1, which increases cytotoxicity of CD8⁺ T cells. GSK-3 is constitutively active in resting T cells.² SB415286, an small inhibitor against GSK-3, competitively inhibits both isoforms alpha and beta isoform.³ Similarly, inhibition of GSK-3 catalytic activity with SB415286 increased the killing efficiency of cytotoxic T lymphocytes (CTLs). T-bet , which is a transcription factor, represses the expression of PD-1 and sustain virus-specific CD8⁺ T cell responses during chronic infection. Further, the injection of anti-PD-1 antibody did not increase the CTLs response further in mice injected with SB415286 and vice versa. Besides, the inactivation of GSK-3 in vivo can significantly reduce the progression of Murid herpesvirus 68 (MHV-68) infection due to reduced PD-1 expression. Inhibition of the GSK-3 also regulates the expression of PD-1 during lymphocytic choriomeningitis virus clone 13 strain (LCMVCl13) chronic infection. In conclusion, GSK-3 inhibitor may be used as a PD-1 modulator in T cells immunity.

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