Lecture 29; Trained Immunity

Question 1

Whats this emerging area of immunology?

Answer 1

The idea that the adaptive immune system can be trained.

Largely monocytes and macrophages, although some evidence for DCs

Specifically the evidence that a monocyte can have a heightened response to a pathogen following a previous exposure (broad memory)

Named as;
- Trained immunity or innate memory

Question 2

Where does a lot of evidence come from for trained immunity?

Answer 2

vaccination studies

Question 3

Whats driving the trained immunity?

Answer 3

Epigenetic changes

Question 4

What two species are looked at today for main experimental evidence?

Answer 4

Droosphilia (no adaptive response)

Flat worms (no adaptive)

Question 5

What does the use of S. pneumoniae in drosophilia demonstrate?

Answer 5

A sub-lethal infection with S. pneumoniae protects against reinfection with a lethal dose

Question 6

How long after giving the sub lethal S. pneumoniae dose did the protection last?

i.e how long can they wait till they give the next dose and get the same protection?

Answer 6

They found the increased protection is long lived (14 days in this experiment)

(long term for the drosophila)

Question 7

What two pathways did they test for being responsible for this heightened response?

Answer 7

Two pathways;

PGRP (like TNF)

and

TLR (peptidoglycan acts on this IMP.)

Antimicrobial pathways in Drosophila

Both act on NFkB

Question 8

Which pathway was responsible for the heightened protection?

Answer 8

In Drosophila protection is specific for S. pneumoniae and dependent on the Toll pathway

Question 9

What other invertebrate had elevated resistance to reinfection?

Answer 9

Planarians infected with Staphylococcus have elevated resistance to re-infection

Termed; Instructed Immunity

Question 10

In the planarians, what did they find trained immunity was dependant on?

Answer 10

Trained immunity dependent on a specific peptidoglycan recognition protein

Question 11

What early evidence for trained immunity in humans?

Answer 11

The BCG vaccine for TB

Question 12

For BCG what reduces the odds of getting TB?

Answer 12

A specific immune response is not the protective mechanism

Question 13

What was shown in mice regarding C. albicans?

Answer 13

If a mouse was injected with an A viralent strain then two weeks later with the viralent strain it was protected.

Not T cell dependant. (knockout)

If they knockout Monocytes, macros then they dont get this response

Question 14

Whats required for trained immunity?

Answer 14

Macrophages

Question 15

What happens with the C albicans when they knocked out T cells?

Answer 15

They had the same protective response therefore this process is independent of T cells. (shown in mice)

Question 16

What is epigenetics?

Answer 16

• Now defined as the study of heritable changes in genome function without alteration to DNA sequence
• DNA modifications-methylation of cytosine residues
• Histone modifications- methylation, acetylation, phosphorylation

Can also modify Histone moelcules (the things that wrap up DNA)

Question 17

What did they show when they gave LPS to the mouse primed from C. albicans?

Answer 17

That IL6 and TNFa were still heightened indicating that this trained immunity is broad recognition

Question 18

What did invitro training of innate immunity show?

Answer 18

Trained monocytes have elevated production of pro-inflammatory cytokines (protection is broad)

Used range of PAMPS

Question 19

What happened when they gave dead C. albicans and what did they find when they further isolated it?

Answer 19

Found that its the component of the cell wall that triggers this immunity training.

specifically; b-glucan alone can induce the trained phenotype

NOT MANNAN

Question 20

What causes the range of macrophage phenotypes?

Answer 20

Epigenetic changes known to underpin macrophage functional heterogeneity

Changes in promoters (some act. some deact.)

Question 21

What did they bind B glucan did to the epigenetics?

Answer 21

b-glucan alters epigenetic landscape in trained monocytes

specifically changes in H3K4me3 (methylation)

Question 22

What epigenetics / genes were altered?

Answer 22

H3K4me3 marks elevated at promoter regions of important pro-inflammatory cytokines and PRRs

Question 23

What did the epigenetic changes do?

Answer 23

Initial activation associated with specific marks
• Some marks remain after elimination of pathogen (latent enhancers)
• A stronger response upon re- challenge

Question 24

Are all epigenetic changes to monocytes good?

Answer 24

No, some PAMPS can cause;
- unresponsiveness, immunotolerance

I.e low dose LPS
“endotoxin tolerance’

While others;
- heighten the inflam response

Question 25

What was found to be essential for trained immunity?

Answer 25

Aerobic glycolysis necessary for functional reprogramming during trained immunity

Question 26

What can changes in metabolic mode do in training stimuli?

Answer 26

Training stimuli induce changes in cellular metabolism that can influence epigenetic enzymes

Question 27

What are the possible therapeutic uses?

Answer 27

Activation:
• e.g. new more effective vaccines
• Treatment of infections in infants (within 1st 3 months)
• Treatment of immune paralysis
Suppression:
• e.g. acute or chronic inflammatory diseases