trained Immunity

Question 1

Innate immunity - first line defence

Answer 1

Immediate, broad response
Time - minutes to hours post infection
PRRs - TLRs, NLRs, RLRS
Recognise PAMPs and DAMPs
No somatic recombination

Question 2

Cellular players of innate immunity

Answer 2

Macrophages - phagocytosis, cytokine production
Neutrophils - rapid infiltration, ROS production
Dendritic cells - antigen presentation, cytokine signalling
NK cells - cytotoxicity against infected/stressed cells

Question 3

Effector functions of innate immunity

Answer 3

Phagocytosis
Cytokine/chemokine release eg TNF-alpha
Complement activation

Question 4

Innate memory

Answer 4

Trained immunity - monocytes and macrophages
NK cells memory - recall responses

Question 5

What is trained immunity?

Answer 5

A form of innate immune memory - enhanced, non specific response upon restimulation

Question 6

Factors of trained immunity

Answer 6

Not antigen specific - no Clonal expansion
Involves epigenetic and metabolic reprogramming
Effects can persist for weeks or months, even in short lived cells

Question 7

Metabolic reprogramming - mechanism of trained immunity

Answer 7

Shift from oxidative phosphorylation in naive cells to glycolysis in trained cells
This is known as Warburg effect
Increased Krebs cycle intermediates and lipid changes support cytokine production

Question 8

Epigenetic reprogramming - mechanism of trained immunity

Answer 8

Chromatin becomes more open which enables faster transcription.
Trained cells at rest show H3K4me1 priming which enables rapid activation on exposure

Question 10

Cellular targets of trained immunity

Answer 10

Monocytes/macrophages - short term
HSPCs haemopotic stem and progenitor cells in bone marrow - long term reprogramming

Question 11

Cytokine induced memory like NK cells - mechanism of NK cell memory

Answer 11

Triggered by IL-12, 15, 18
Epigenetic priming of IFN-y and cytotoxic genes

Question 12

Antigen specific NK memory

Answer 12

NKG2C+ NK cells in human cytomegelovirus

Question 13

Tissue resident NK memory

Answer 13

Liver resident NK cells respond to haptens which produce stress signals and cause local inflammation

Question 14

Trained immunity stimuli

Answer 14

Beta glucans - dectin-1 pathway
BGD vaccine - NOD2 pathway
Oxidised LDL - causes atherosclerosis

Question 15

NK memory stimuli

Answer 15

Cytokines IL-12,15,18
Viral antigens eg HCMV - NKG2C
Haptens
Tumour ligands

Question 16

Implications for vaccines in trained immunity

Answer 16

It can act as a broad acting adjuvant
BCG vaccine shows non specific protection against respiratory infections

Question 17

Implications for infection

Answer 17

Enhanced early innate response that reduces pathogen burden
NK memory improves viral control

Question 18

Implications for cancer

Answer 18

Memory NK cells are being explored for adoptive cell therapy

Question 19

Implications for chronic disease

Answer 19

Maladaptive trained immunity contributes to
Atherosclerosis
Autoimmunity