Cell Movement and Leukocyte Migration Notes

Why is it important?
- Deliver cells to tissues or site of infections.
- Myeloid cells from blood to tissues.
- Lymphocytes from:
  - Primary lymphoid organs to secondary lymphoid organs.
  - Secondary lymphoid tissues to sites of infection.
- Immune response initiated at one site and delivered at another.

How do cells know where to go?
- Immune cells.
- Infected tissue.
- Adhesion molecules.
- Chemokines.

Homing: General leukocyte movement from blood into tissues.
Migration or Recruitment: Blood $\rightarrow$ Specific site.
Recirculation: Blood $\rightarrow$ Secondary lymphoid organs $\rightarrow$ Blood.

Heterodimeric surface proteins.
- > 15 types of α chains and 7 types of ß chain.
- > 30 different integrins.
Integrate signals between extracellular ligands and cellular function associated with cytoskeleton-dependent motility/shape/phagocytosis.
Increase their affinity for ligands upon intracellular signals.

Chemo-tactic cytokines.
Different cells express different chemokine receptors - this allows the cell to respond to different chemokines.
Follow the chemokine gradient.

Tissue resident cells promote inflammation.
TNF and IL-1 stimulate endothelial cells to rapidly express two adhesion molecules - E-selectin & P-selectin.
- Circulating phagocytes express surface carbohydrates that bind weakly to the E-selectin and P-selectin - causes the cells to “roll” along the endothelium.
Leukocytes express integrins
- Integrins "integrate" extrinsic signals into cytoskeletal alterations
- At sites of infection, resident cells produce chemokines
  - stimulate a rapid increase in the affinity of the leukocyte integrins for their ligands on the endothelium.
  - direct the migration of cells
- The firm binding of integrins to their ligands arrests leukocyte rolling.
The cytoskeleton of the leukocyte is reorganized, and the cell spreads out on the endothelial surface.
- Firm adhesion is quickly followed by extravasation into the inflamed tissue.
- Chemokine-directed migration tells the leukocytes where to go.

Express specific homing receptors that allow them to recirculate between lymphoid tissue.
- L-selectin: binds a ligand expressed on high endothelial venules (HEV).
- CCR7: a chemokine receptor that allows naive T cells to home to the specific chemokine CCL19/21 (previously called MIP-3β) expressed by HEV.
- Integrins (LFA-1): bind ICAM-1; "integrate" extrinsic signals into cytoskeletal alterations allowing firm adhesion.
This combination permits naïve T cells to enter and recirculate through secondary lymphoid tissues.
Naive T cells:
- CD4/8+ T cell receptor+ CCR7+ L-selectin+ LFA-1+
Naive T cells that have homed into lymph nodes but fail to recognise antigen and to become activated will eventually return to the blood stream.

Provides naive T cells with another chance to enter secondary lymphoid tissues and search for the antigens they do recognise.
The major route of blood re-entry is:
1. through the efferent lymphatics (perhaps via other lymph nodes in the same chain),
2. through the lymphatic vasculature to the thoracic or right lymphatic duct
3. finally into the superior vena cava or right subclavian vein

Naive T cells need to be given time to inspect DC for antigen-MHC complexes.
Recently arrived naive T cells express low levels of sphingosine 1 phosphate receptor 1 (S1PR1).
- Because engagement with S1P in blood leads to S1PR1 internalisation.
- This means they are unable to respond to the high concentrations of S1P (a lipid chemoattractant) in the medullary sinus, efferent lymphatics, and blood.
- The S1P gradient is maintained (and is therefore low in tissues) because an S1P-degrading enzyme, S1P lyase, is ubiquitously present in tissues.
If naive T cells do not engage with their cognate antigens after several hours, they will re-express S1PR1 on their surface.
- allowing them to respond to the S1P gradient and egress from lymph nodes.

Leukocyte migration from blood into tissues occurs through postcapillary venules and depends on chemokines and adhesion molecules expressed on the leukocytes and vascular endothelial cells.
Selectins are carbohydrate-binding adhesion molecules that mediate low-affinity interaction of leukocytes with endothelial cells, the first step in leukocyte migration from blood into tissues. Integrins are a large family of adhesion molecules, some of which mediate tight adhesion of leukocytes with activated endothelium.
Chemokines are a family of proteins that regulate when and how leukocytes migrate into tissues, and organise the functional locations of lymphocytes and DCs in lymphoid organs, and bind to chemokine receptors on leukocytes, which signal to increase leukocyte integrin affinity and stimulate leukocyte movement along a concentration gradient.
Different types of leukocytes and at different stages of differentiation express distinct sets of chemokine receptors, and the types of chemokines present in tissues or on endothelial cells varies with different inflammatory states and tissue types.
Recently arrived naïve T cells express low levels of sphingosine 1 phosphate receptor 1 (S1PR1) thus are unable to respond to the high concentrations of S1P in the medullary sinus, efferent lymphatics and blood.