The kinase AKT1 potentiates the suppressive functions of myeloid-derived suppressor cells in inflammation and cancer

Myeloid-derived suppressor cells(MDSCs)are a group of heterogeneous cells1 that play crucial negative regulatory roles in immune-associated diseases,including infections,2 cancer,3 transplantation4,and autoimmunity.5 We and others have shown that mTOR signaling and its downstream metabolic pathways regulate MDSC recruitment and function in inflammation and autoimmunity.

Glucocorticoid receptor promotes the function of myeloid-derived suppressor cells by suppressing HIF1α-dependent glycolysis

Immunomodulatory signaling imposes tight regulations on metabolic programs within immune cells and consequentially determines immune response outcomes.Although the glucocorticoid receptor(GR)has been recently implicated in regulating the function of myeloid-derived suppressor cells(MDSCs),whether the dysregulation of GR in MDSCs is involved in immune-mediated hepatic diseases and how GR regulates the function of MDSCs in such a context remains unknown.Here,we revealed the dysregulation of GR expression in MDSCs during innate immunological hepatic injury(IMH)and found that GR regulates the function of MDSCs through modulating HIF1α-dependent glycolysis.Pharmacological modulation of GR by its agonist(dexamethasone,Dex)protects IMH mice against inflammatory injury.Mechanistically,GR signaling suppresses HIF1αand HIF1α-dependent glycolysis in MDSCs and thus promotes the immune suppressive activity of MDSCs.Our studies reveal a role of GR-HIF1αin regulating the metabolism and function of MDSCs and further implicate MDSC GR signaling as a potential therapeutic target in hepatic diseases that are driven by innate immune cell-mediated systemic inflammation.

Crucial role of histone deacetylase SIRT1 in myeloid-derived suppressor cell-mediated reprogramming of CD4^(+) T-cell differentiation

Myeloid-derived suppressor cells(MDSCs)are heterogeneous,immature myeloid cells that inhibit the immune responses of T cells.1–5 MDSCs play a crucial role in infection,6,7 transplantation,8,9 autoimmune diseases10,11,and tumors12,13 by driving the differentiation of specific T-cell subsets,but the precise regulatory mechanism is still unclear.Recently,our results showed that SIRT1,a histone deacetylase,suppresses the functions of proinflammatory MDSCs and promotes tumor growth.14 However,it remains unclear whether SIRT1 regulates the MDSC-induced differentiation of T cells.Here,we identified the regulatory effects of SIRT1 in CD11b+Gr1+MDSCs on T-cell differentiation.