4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8^(+) T cell proliferation

4-1BB(CD137)is a strong enhancer of the proliferation of CD8^(+)T cells.Since these cells require increased production of energy and biomass to support their proliferation,we hypothesized that 4-1BB signaling activated glucose and fatty acid metabolism.We found that treatment with agonistic anti-4-1BB mAb promoted the proliferation of CD8^(+)T cells in vitro,increasing their size and granularity.Studies with a glycolysis inhibitor and a fatty acid oxidation inhibitor revealed that CD8^(+)T cell proliferation required both glucose and fatty acid metabolism.Anti-4-1BB treatment increased glucose transporter 1 expression and activated the liver kinase B1(LKB1)-AMP-activated protein kinase(AMPK)-acetyl-CoA carboxylase(ACC)signaling pathway,which may be responsible for activating the metabolism of glucose and fatty acids.We also examined whether blocking glucose or fatty acid metabolism affected cell cycle progression and the anti-apoptotic effect of 4-1BB signaling.The increase of anti-apoptotic factors and cyclins in response to anti-4-1BB treatment was completely prevented by treating CD8^(+)T cells with the fatty acid oxidation inhibitor,etomoxir,but not with the glycolysis inhibitor,2-deoxy-D-glucose.We conclude that anti-4-1BB treatment activates glucose and fatty acid metabolism thus supporting the increased demand for energy and biomass,and that fatty acid metabolism plays a crucial role in enhancing the cell cycle progression of anti-CD3-activated CD8^(+)T cells in vitro and the anti-apoptotic effects of 4-1BB signaling on these cells.

4-1BB signaling beyond T cells

Originally discovered as a T cell-activating molecule,4-1BB(CD137)is now also recognized as an activator of non-T cells,thus imparting a new dimension to its potential in vivo effects.4-1BB expression is seen on a variety of non-T cells including activated dendritic cells(DCs),monocytes,neutrophils,B cells and natural killer(NK)cells,and promotes their individual effector functions.The T cell-and non-T cell-activating ability of 4-1BB may be the basis of its powerful anti-cancer,anti-autoimmune and anti-viral effects.Here we discuss the consequence and importance of 4-1BB signaling in non-T cells.We consider its effects on immune regulation,and the distinct and/or overlapping pathways involved in these responses,as well as possible therapeutic applications.