T cell metabolism and immune function

Question 1

How activated T cells change their metabolism?

Answer 1

1. Increased uptake of glucose (aerobic glycolysis)
2. Altered mitochondrial function (increased mitochondrial activity)
3. Altered amino acid metabolism (they take up more amino acids)

Question 2

Aerobic glycolysis

Answer 2

Glycolysis, even in the presence of oxygen
- Cells take up glucose
- They metabolise it, 2 molecules of glucose to 2 molecules of pyruvate
- They reduce pyruvate to lactate and excrete it

Question 3

Why activated immune cells do aerobic glycolysis?

Answer 3

• It enables a rapid influx of of glucose through glycolysis
• A lot of intermediates being produced which can feed into different biosynthetic pathways
• Needed for proliferation

Question 4

Why activated immune cells increase glucose uptake?

Answer 4

• Production of biosynthetic intermediates of glycolysis for proliferation
• Acetylation of histones for gene transcription
• Translation of mRNA for protein synthesis

Question 5

Acetylation of histones

Answer 5

Glucose-derived acetyl-CoA leads to acetylation of histones. Acetylation of histones makes DNA more accessible for transcription factors to bind and allow expression of genes.

Question 6

Translation of mRNA

Answer 6

GAPDH, when not engaged in the glucose metabolism it binds to mRNA and stops it from translating. When GAPDH is engaged in glucose metabolism it releases mRNA and allows it to be translated. Increased protein synthesis.

Question 7

ECAR

Answer 7

• Extracellular acidification rate
• It reflects the production of lactate from glucose.
• Lactate is excreted from the cell as lactic acid, which acidifies the cell culture medium
• Measure the changes in rate of acidification as surrogate of lactate production

Question 8

Increased mitochondrial function

Answer 8

• Take up a lot of glucose, fatty acids and glutamine to fuel the TCA cycle to generate more ATP
• Upregulation of IL-2 for proliferation
• Generation of nucleic acids for proliferation and synthesis on DNA and RNA

Question 9

Upregulation of IL-2

Answer 9

Increased activity of electron transport chain leads to increased production of reactive oxygen species which stabilise NFAT. NFAT transports to the nucleus and promotes expression of genes encoding IL-2. IL-2 is an important growth factor for T cells.

Question 10

Generation of nucleic acids for DNA and RNA synthesis

Answer 10

Activated T cells create more mitochondria, which are specialised to generate purines and thymidine which supports proliferation by generating nucleic acids needed for DNA and RNA synthesis.

Question 11

Increased uptake of amino acids

Answer 11

They take up substantially higher levels of amino acids upon activation.

Question 12

Why increased uptake of amino acids?

Answer 12

• Increased protein synthesis - alanine
• Activation of mTORC - arginine and leucine
• Fuel TCA cycle - glutamine
• Purines synthesis - serine

Question 13

Glucose metabolism

Answer 13

• 1 molecule of glucose
• 2 molecules of pyruvate
• either reduce to lactate, and excrete
• or convert to acetyl-CoA
• oxidisation in mitochondria in TCA cycle
• NADH and FADH2 oxidisation
• Activation of electron transport chain
• 32 molecules of ATP

Question 14

mTORC

Answer 14

• Key regulator of immune metabolism
• Leads to increased uptake of glucose
• Leads to increased protein synthesis
• Can be activated by signalling through CD28 or CD46
• Can be activated by arginine and leucine

Question 15

Th1 and Th17 cells metabolism

Answer 15

• Highly glycolytic
• Increased uptake of glutamine

Question 16

Tregs and memory T cells metabolism

Answer 16

• Dependent on fatty acid metabolism
• Memory T cells have large complex mitochondria, they have increased capacity and tolerate different tissue environments.
• Fusion of mitochondria into complexed mitochondria is directed by Opa1
• Deletion of Opa1 leads to no complexed mitochondria and no memory

Question 17

What signals are important for metabolic changes?

Answer 17

• CD28 -> PI3K -> pAkt -> mTORC
• C3b -> CD46 -> mTORC

Question 18

Immune metabolism in cancer

Answer 18

• tumour cells and TAMs deplete glucose from the TME which leads to T cells hypo-responsiveness
• Mitochondrial function becomes impaired by chronic antigen stimulation
• build-up of metabolic waste products can be suppressive to T cells

Question 19

Immune metabolism in autoimmunity

Answer 19

• increased glycolysis
• increased mitochondrial function
• MS, SLE and T1D

Question 20

Immune metabolism in infection

Answer 20

• Metabolic dysfunction
• Mitochondrial dysfunction
• Due to chronic antigen stimulation
• Increased mTORC activity promotes viral replication

Question 21

Targeting T cells in anti-tumour immunity

Answer 21

• ICI to modulate the balance of glucose uptake in TME
• Oncolytic virus expressing leptin can promote T cell metabolic activity

Question 22

Targeting T cells in autoimmunity

Answer 22

• Inhibition of mitochondrial function and glycolysis