USE OF GSK-3 INHIBITORS OR ACTIVATORS WHICH MODULATE PD-1 OR T-BET EXPRESSION TO MODULATE T CELL IMMUNITY

摘要

The present application generally relates to the discovery that glycogen synthase kinase 3 (GSK-3) is an upstream signalling molecule that controls PD-1 transcription and Tbet expression by immune cells and in particular T-cells. Based on this discovery, and in view of the known immunosuppressive effect of PD-1 on immunity and the promoting effect of Tbet on T cell immunity, the present invention relates to the use of GSK-3 inhibitors to promote immunity, including cytotoxic T cell immunity in subjects in need thereof, especially subjects with chronic conditions wherein inhibiting PD-1 expression and/or blockade or Tbet upregulation is therapeutically desirable such as cancer and infectious conditions. Further, based on this discovery the present invention relates to the use of compounds which promote GSK-3 expression or activity to suppress immunity, especially aberrant T cell immunity in subjects in need thereof, e.g., subjects with chronic conditions wherein PD-1 upregulation or Tbet down regulation is therapeutically desirable such as allergic, autoimmune or inflammatory conditions. Also, screening methods for identifying immune agonists and antagonists, especially antibodies, are provided.