Metabolic Control of Dendritic Cell Functions: Digesting Information

In conclusion, a delicate balance of the complex system of nutrient sensing and mTOR (mTORC1) signaling is crucial to ensure appropriate development of DCs (23). Strikingly, loss of both mTOR complexes results in opposite effects on in vivo DC development compared with loss of mTORC1 alone, probably indicating differential inhibition of mTOR downstream targets and collaboration of mTOR complexes. Indeed, DC loss upon TSC1 deficiency is accompanied by increased DC apoptosis and enhanced metabolic activity due to TSC1-dependent inhibition of Myc, an effector downstream of mTOR (Figure 1), and reversed upon Myc loss (35). Of note, Myc itself regulates glucose and glutamine catabolism in activated T cells (37). Moreover, apart from controlling mTORC1 activity, AMPK is an important regulator of fatty acid metabolism limiting ACC1/2 activity (Figure 1), which is crucial for T cell activation (38). AMPK loss generally favors cytosolic FAS over mitochondrial FAO, which likely accounts for the decrease in differentiation in AMPKα1-deficient cDC1s, as this process was shown to be sensitive to FAO block (18) and, hence, could be independent from mTOR signaling. Moreover, the context dependence of balanced mTOR signaling in DCs may be strongly influenced by FLT3L. First, rapamycin and Mst1/2 deficiency have different or even opposing effects on DC generation in the steady state compared with FLT3L-mediated DC expansion in vivo (21, 25, 30). Second, while FLT3L-mediated different...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research