T cell metabolism Flashcards
what is the role of T cell metabolism?
- T cells need to use energy to function
- T cells need to proliferate very fast
- T cells need to do different jobs at different times of the immune response
what is the role of IL-2 receptors on T cells?
controls the level of immune response
what is the role of cytokines in T cells?
They can protome different metabolic pathways in T cells
how do T cells use metabolic pathways?
-generate energy stores to promote survival
- produce everything they need for growth and proliferation
how is metabolism and fuel linked?
Metabolic pathways are closely linked by shared fuel inputs
what are the six major metabolic pathways?
- glycolytic metabilic pathway
- TCA cycle
- pentose phosphate pathway
- fatty acid oxidation
- fatty acid synthesis
- amino acid metabolic pathways
what is the role of glycolysis?
converts glucose into pyruvate
what happens to pyruvate in metabolism?
Pyruvate is converted into lactate and secreted or feed into the TCA cycle
what does the TCA cycle result in?
Leads to NADH and FADH2, for electron transport chain, which leads to ATP prodcution
what happens in Glycolysis?
Feeds PPP which generates ribose for nucleotides, amino acids and NADPH
what is NADPH used for?
fatty acid synthesis, which uses citrate from the TCA cycle
what happens when fatty acids are oxidised?
fatty acid oxidation leads to generation of NADH and FADH2
what is the role of amino acid synthesis?
- can feed the TCA cycle
- important for cell growth and protein biosynthesis
what metabolic pathways are involved in oxidative phosphorylation?
- fatty acid synthesis
- fatty acid oxidation
- TCA cycle
what metabolic processes are involved in glycolysis?
- glycolytic metabolic pathway
- amino acid metabolic pathways
how is glycolysis utilised in T cells?
- Relatively inefficient, but supports anabolic growth
- Pro-growth signal pathways (PI3K and MAPK) promote use of glycolytic metabolism
Most important metabolism for rapidly proliferating cells
when do T cells switch to glycolysis?
when they need to do stuff very quickly
what are pro-growth signal pathways?
PI3K
MAPK
how do T cells utilize the TCA cycle?
- Used in most quiescent or non-proliferating cells
- Highly eficient
- Supports oxidative phosphorylation (OX-PHOS)
what is fatty acid oxidation?
Conversion of fatty acids into products the cell uses to generate energy
what is fatty acid synthesis?
lets cells make lipids as building blocks for cell growth and proliferation
how does T cell subset effect metabolism?
The ability of a T cell to transition from a naive, to an effector, to a memory phenotype is dictated by metabolism.
- Specific T cell subsets require distinct energetic and biosynthetic pathways to match their function requirements
- Metabolic program vaires to match the T cell subset in order to enable cell survival and function
what is the metabolism used in T cell activation?
aerobic glycolysis (and glutamine catabolism)
what mediates the switch of T cell metabolism to aerobic glycolysis?
Switch is mediated by signalling pathways downstream from TCR, costimulation, and cytokines
Involved MAPK/ERK, PI3K, mTOR, NF-KB
- leads to activation of transcription factors Myc and HIF-1alpha
- induces genes important for glycolysis
*all mediated by mTOR
what is the metabolism of Naive T cells?
No proliferation, no effector function
= minimal energy requirements
Low nutrient consumption (glucose) and OX-PHOS
what are the metabolic changes in activated (effector) T cells?
Need for rapid proliferation and effector function
- glycolysis for cytokine production
- OX-PHOS for proliferation
what controls changes in metabolism as T cells activate?
TCR signalling cascade
Presence of cytokines
availability of nutrients
what is the role of GLUT-1 in effector T cells?
-glucose transport
-expression upregulated upon activation
-expression dependent on activation of Akt by PI3k
what is the role of PI3K in T cell activation?
Activates mTOR
what is the role of mTOR is effector T cell metabolism?
signalling augments glycolytic metabolism to support growth and proliferation
what are the different energy sources for T cells?
- glucose
- glutamine
- Lipids or fatty acids
how do T cells utilise glucose as an energy source?
T cell in activated by GLUT-1 to the cell surface
Important in early activation - e.g. expressing activation markers and increasing cell size
how do T cells utilise glutamine as an energy source?
T cells increase the expression of glutamine transporters
- Deletion of glutamine transporters impairs the transition to an effector T cell
how do T cells utilise lipids or fatty acids as an energy source?
- component of cell membranes
- provide a high yielding energy source
- supply substrates for cell signalling
After T cell activation, the demand for lipids rapidly increases (for synthesis of membranes)
why do different T cell subsets make different cytokines?
They make different cytokines because they have different roles during infection
what happens when their is no GLUT-1 in T cells?
- T cells can’t grow and proliferate
- T cells can’t differentiate into Th1, Th2 or Th17
- they can still differentiate into Tregs
what does mTOR activate in T cell metabolism?
mTOR activated downstream of TCR/costimulation/IL-2
- Cells swith to glycolysis
two different mTOR complexes
- same protein can do different things and be regulated by different stimuli
what are the different types of mTOR?
mTORC1
mTORC2
what is the function of mTORC1?
- cell growth and division
- responds to nutrient availability
what is the funcion of mTORC2?
-responds to growth factors and cytokines
how do Tregs produce energy?
by fatty acid oxidation and OX-PHOS
