Immune Cell Migration Flashcards
what is the afferent lymphatic?
into the lymph nodes
what is the efferent lymphatic?
out of the lymph nodes
what is a key problem for the immune system?
- pathogens can establish anywhere
- Needs T and B cells to detect the pathogens
- these cells are highly specific and therefore are very rare
- to solve this immune cells circulate the blood and the lymph
- to get cells to the right place you need chemokines and adhesion molecules
what are chemokines?
chemotactic cytokines
- secreted molecules that bind to cell surface GAGs
- chemokines bind back to the cells that produce
how is a chemokine gradient formed?
- have the highest chemokine concentration on its surface
- any that dont bind become tethered to the ECM proteins
- tethered chemokines form immobilised concentration gradient
how are chemokines sense?
- target cells express chemokine receptors
- chemokine receptors are coupled to heterotrimeric G proteins
what is the structure of a chemokine receptor?
- alpha, beta and gamma
- alpha is bound to GDP
- when chemokine binds it causes a conformational shift, causes activation
- G proteins associate
- exchange GDP for GTP which initiates a signalling cascade
what happens when a chemokine binds to a receptor?
there is cytoskeletal rearrangement and the cell migrates
what is a CC chemokine?
- towards the end terminus they have cysteine residues
- involved in disulphide bonds
what is a CXC chemokine?
got cysteine residues but with any amino acid in between
what kind of leukocytes can be found in the blood?
T cells; CD4 and CD8, B cells, neutrophils, monocytes
what is lymphatic circulation?
- lymph transmits signals from tissues to draining lymph nodes
- carry lymph from peripheral tissues to draining lymph nodes
- transports immune cells, intact pathogens, free antigens
where are adaptive immune responses initiated?
in draining lymph nodes
why does the lymph node also have blood vessels?
- T cells can either circulate or they can interact and migrate into the lymph node
- this would be the HEV (high endothelial vessel)
- carry signals, dendritic cells which interact with T cells
how do T cells exit the blood and enter the lymph node?
- blood vessels convert into HEV
- T cells can interact
- EXTRAVASATION
- blood moves quickly, cells need to slow down
- rolling, activation, firm adhesion, transmitgration
what is rolling (stage 1 of extravasation)?
- lectin dependent
- Naive T cells express cell surface protein L selectin (CDG2L)
- binds to carbohydrates on endothelial cells on HEV, recognises the glycoproteins
- different lymph nodes can have different glycoproteins
what are HEV surface glycoproteins called in rolling?
‘addressins’
what are the addressins found on HEV in rolling?
GlyCAM
CD34
what are PNAd in rolling?
- peripheral node addressins
- addressins for peripheral lymph nodes are PNAd
in rolling what is the interaction between L selectin and PNAd like?
weak/transient (on/off kinetics)
what is activation and firm adhesion (stages 2 and 3 of extravasation)?
- chemokines convert rolling to firm adhesion
- have chemokines on the surface of HEV
- display 2 chemokines on its surface GAGs (CCL19 and CCL21)
- naive T cell express CCR7, the receptor for CCL19 and CCL21
how does chemokine signalling lead to integrin activation in activation and firm adhesion?
- T cells have integrin LFA1 on their surface
- endothelial cells have adhesion molecule ICAM1
- LFA1 has alpha1 and beta2
- LFA1 binds to ICAM1
- chemokines signalling activates and causes a conformational shift in surface integrin’s
- conversion to high affinity ICAM1 binding = firm adhesion
what structure do integrins have?
heterodimers
alpha and beta subunits
why does activation and firm adhesion in extravasation need signalling?
in the absence of signalling LFA1 and ICAM1 the interaction is very weak, LFA1 starts in a low affinity conformation
