Distinct strengths of mTORC1 control T-cell memory via transcriptional FOXO1 and metabolic AMPKα1 pathways in linear cell differentiation and asymmetric cell division models

The Critical Role of AMPKα1 in Regulating Autophagy and Mitochondrial Respiration in IL-15-Stimulated mTORC1Weak Signal-Induced T Cell Memory: An Interplay between Yin (AMPKα1) and Yang (mTORC1) Energy Sensors in T Cell Differentiation

“…A linear cell differentiation (LCD) model was originally proposed by Sallusto’s group in 2000, in which different weak and strong strengths of immune stimuli regulate T-cell differentiation into long-term T M and short-lived T E cells, respectively [ 37 ]. Accumulating evidence strongly supports this well-known model of different strengths of stimuli in programming T E - and T M -cell differentiation [ 4 ]. However, the underlying molecular mechanism(s) regulating the distinct T-cell differentiation programs in LCD remains elusive.…”

“…To further characterize the downstream responses to IL-15 stimulation of mTORC1 Weak signaling, we quantified the relative abundance of several transcription factors with known roles in T E and T M cell formation by Western blotting. IL-15/T M cells with mTORC1 Weak signaling had significantly higher levels of FOXO1, TCF1, Eomes, cMyb and Id3 crucial for T M -cell phenotype and differentiation, while the abundance of Blimp1, Id2, T-bet, ZEB2 and cMyc central to T E -cell phenotype, and differentiation [ 3 , 4 ] was significantly lower ( Figure 2 B). IL-2/T E cells with mTORC1 Strong signaling exhibited the reciprocal transcription factor expression profile ( Figure 2 B).…”

“…Various transcription factors and kinases crucial to controlling T-cell phenotype and differentiation have been identified. The transcription factors forkhead box-O-1 (FOXO1), T-cell factor-1 (TCF1), inhibitor of DNA binding-3 (Id3), cMyb and Eomes all play important roles in T M -cell differentiation [ 3 , 4 ]. The adenosine monophosphate-activated protein kinase-α1 (AMPKα1), an evolutionarily conserved energy sensor, is crucial for controlling cellular metabolism and survival by activating various regulators of autophagy and mitochondrial respiration to meet increased energetic demands.…”

“…AMPKα1 also promotes the fusion of individual mitochondria by inducing a shift from dynamin-related protein-1 (DRP1)-regulated fission events to optic atrophy-1 (OPA1)-controlled mitochondrial fusion events, which in turn stimulates the expression of several players critical to mitochondrial biogenesis and a switch in fuel preference to fatty acid oxidation (FAO). These AMPKα1 targets include peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), aquaporin-9 (AQP9), carnitine palmitoyl transferase-1α (CPT1α), Complex I of electron transport chain (ETC) and mitochondrial transcription factor-A (TFAM) [ 4 , 5 , 6 ]. The mammalian target of rapamycin complex-1 (mTORC1) is another evolutionarily conserved energy sensor that controls the activity of ribosomal S6 kinase (S6K) and eukaryotic translation initiation factor-4E (eIF4E), two downstream substrates crucial to the modulation of T-cell proliferation, differentiation, metabolism and survival [ 7 ].…”

“…The mammalian target of rapamycin complex-1 (mTORC1) is another evolutionarily conserved energy sensor that controls the activity of ribosomal S6 kinase (S6K) and eukaryotic translation initiation factor-4E (eIF4E), two downstream substrates crucial to the modulation of T-cell proliferation, differentiation, metabolism and survival [ 7 ]. mTORC1 also activates the transcription factors Blimp1, Id2 and T-bet, which are pivotal to the T E -cell phenotype and differentiation, as well as cMyc and hypoxia-inducible factor-1 (HIF-1α), which are central to the reliance of T E cells on the glycolytic metabolism [ 3 , 4 , 7 ]. However, AMPKα1- and mTORC1-dependent molecular pathways that regulate CD8 + T-cell memory have yet to be fully explored.…”