Lecture 15 – Regulation of immune cell interactions

Resting dendritic cells are not very phagocytic as they haven’t been activated yet.

True or False.

False.

Resting dendritic cells are extremely phagocytic

• They are actively taking in molecules around them and searching for antigens 

Stimulation by which cytokine has been shown to reduce DC phagocytic activity?

• IL-1B

Activation of DCs with what can result in DC activation and a reduction in phagocytic activity?

Bacillus Calmette-Guérin (BCG) vaccine

Why do activated DCs express more co-stimulatory molecules (e.g. CD80/86)?

More efficient at producing peptides for presentation to and activation of T-cells

Where are most resting T-cells found?

Found inside lymph nodes.

• Activated DCs therefore migrate to lymph nodes

How do DCs move into the lymph vessels?

Drawn into the vessels by following a gradient of chemokines. 

• Lymphatic vessels constantly express CCL21 which attracts CCR7-expressing DCs

Roughly how long does it take activated DCs to migrate into lymph nodes?

~18 hours

Once inside the lymphatic vessels, how do DCs enter the lymph node?

DCs are again drawn across the vessel wall by chemokine gradients

How is the gradient which draws DCs into the lymph node formed?

Two layers of endothelial cells. 

• DCs express CCR7 which recognises CCL21

• The first layer expresses an atypical CCL21 receptor which can bind and degrade the chemokine CCL21

• This forms a gradient where there’s more CCL21 near the ‘bottom’ layer 

• This drives DC movement from the ‘top’ layer to the ‘bottom’ layer and into the lymph node

Once T-cells and DCs meet, the T-cell will respond to the presented antigen most of the time.

True or False.

False.

It’s very rare (1/100,000) that the T-cell will respond to the antigen. 

Once a T-cell eventually recognises the presented antigen, what happens?

T-cell undergoes clonal expansion to make more T-cells which recognise the antigen

These T-cells will then mature and be released.

Why are T-cells ‘trapped’ in the lymph node?

Actively dividing T-cells are not very useful against infections.

• Therefore they are held within the lymph node until they mature

• This is done by inactivation of S1P receptors on T-cells by CD69

• Usually T-cells would follow the S1P gradient out the lymph node

How are T-cells eventually released from the lymph node after being trapped?

• Level of CD69 which blocks S1P receptor action decreases by half with every cycle of mitosis

• After 3-4 divisions, the level becomes so low that S1P can regain function 

• The T-cell can then follow the S1P gradient out the lymph node

How were T-cell divisions followed during the experiment?

Used CFSE which integrates with DNA

• When the cell divides, CFSE divides with it which lets you follow how many T-cell divisions have occurred 

How do B-cells and T-cells enter the lymph nodes?

Through High Endothelial Venules (HEVs)

• Once inside, B-cells and T-cells express receptors for certain chemokines

• They follow chemokine gradients which drives migration towards B-cell follicles or T-cell zones 

How can S1P be used as a therapeutic target?

Possible treatment for auto reactive T-cells

S1P analogues are in clinical trials to try and desensitise the S1P receptor 

• This would cause retention of activated T-cells which could cause autoimmunity

Once outside of lymph nodes, how do T-cells know where they are needed?

In blood vessels, activated T-cells survey the endothelial lining 

• They seek out molecular ‘addressins’ and chemokines which will draw them where they need to go

In the gut, activated DCs migrate where?

Mesenteric lymph nodes

Endothelial cells in the gut express what addressin molecule?

Mucosal addressin cell adhesion molecule-1

• MadCAM-1

T-cells can adhere to MadCAM-1 using what?

T-cells adhere because of expression of α4β7 integrin

• Alpha4beta7

Following binding of MadCAM-1 and α4β7, T-cells still need more signals. What are these?

Interaction between the chemokine CCL25 and the chemokine receptor CCR9 on T-cells

T-cells in the gut express more CCR9 than T-cells elsewhere. Why?

Gut-derived DCs express retinal dehydrogenase which converts vitamin A to retinoic acid

• Presence of retinoic acid induces expression of CCR9 on activated T-cells

Why does expression of CCL25 gradient cause migration of T-cells explicitly to the gut?

CCL25 is expressed by gut epithelial cells.

• Expressed by very few other tissues in the body

How could gut inflammation be controlled by blocking T-cell migration?

Anti-α4β7 antibodies could block T-cell recognition of MadCAM-1 and so prevent T-cell migration.

This could help reduce inflammation in the gut