Lymphocyte trafficking

Question 1

Describe naive lymphocyte circulation

Answer 1

Enter circulation from primary lymphoid organs –> blood –> LNs/secondary lymphoid organs –> lymph –> thoracic duct –> blood (does not reenter primary lymphoid organs

Question 2

Why do naive lymphocytes continually circulate?

Answer 2

• to continually survey for Ag.s
• to distribute the large number of lymphocytes throughout the body

Question 3

Describe how live imaging techniques have demonstrated arrest of CD8+ T cells in the presence of Ag in LN

Answer 3

no peptide:
- lots of movement

some peptide:
- some movement

lots of peptide:
- less movement

Question 4

Describe the tricellular complexes that form in LNs

Answer 4

CD4+ T cell + CD8+ T cell + DC

Question 5

Where do cells enter the LN?

Answer 5

via HEVs

Question 6

Describe where HEVs are found, and when they are developed and the consequences of this

Answer 6

• found in all secondary lymphoid organs except for the spleen
• HEVs don’t develop in a germ free environment –> important for newborns to be exposed to Ag so they develop an immune system

Question 7

What are the three keys to lymphocyte trafficking?

Answer 7

1. cell adhesion molecules –> slow down
2. chemokine R’s –> address
3. S1PR1 –> cycling in and out

Question 8

What are the four families of cell adhesion molecules?

Answer 8

• mucin-like CAMs (e.g CD34) bind to selectins (e.g. L-selectin/CD62L)
• integrins (e.g. LFA-1) bind to Ig superfamily members (e.g. ICAM-1)

Question 9

What are the two major functions of cell adhesion molecules?

Answer 9

1. increase connections between immune cells to facilitate activation responses (e.g. Th + APC)
2. increase leukocyte adherence to endothelium before extravasation, transendothelial migration

Question 10

What are the primary functions of chemokines?

Answer 10

major regulators of leukocyte traffic

Question 11

What are the two types of chemokines?

Answer 11

housekeeping and inflammatory

Question 12

Where do chemokines localize circulating leukocytes to?

Answer 12

1. secondary lymphoid organs
2. specific microenvironments within lymphoid tissues
3. sites of inflammation

Question 13

Describe the R’s that each type of cell has and where this localizes these cells: naive T and B cells; naive T cells; naive B cells; activated B cells; activated T cells

Answer 13

naive T and B cells: CCR7 –> HEV
naive T cells: CCR7 –> T cell zone
naive B cells: CXCR5 –> B cell zone
activated B cells: CCR7 –> T cell zone
activated T cells: various receptors to localize them into specific tissues

Question 14

Describe how rolling, activation, arrest/adhesion, and transendotherlia migration occur

Answer 14

1. rolling
   - L-selectin binds to CD34
   - LFA-1 in low affinity state
2. activation
   - HEV hold chemokines that bind to CCR7
   - CCR7 is activated and activates LFA-1 to high affinity state (sticky)
3. arrest/adhesion
   - LFA-1 binds to ICAM-1

4 transendothelia migration
- LFA-1 is needed for this step
- move from blood to LN

Question 15

What kind of molecule is S1P, what does it bind to?

Answer 15

bioactive lipid that binds to 5 distinct GPCRs (e.g. S1PR1)

Question 16

Describe how lymphocyte trafficking depends on expression levels of S1PR1

Answer 16

1. high [S1PR1] are attracted to high [S1P] in lymph
2. S1P binds to S1PR1 and the R is internalized
3. low S1PR1 expression allows CCR7 expression to increase
4. naive lymphocytes enter LN and remain for hours
5. S1PR1 expression increases, CCR7 decreases –> cells leave LN
6. effector T cell trafficking is also dependent on expression levels of S1PR1

Question 17

Describe the key markers for entry and exit into secondary lymphoid organs for naive T cells and effector T cells

Answer 17

naive T cells:
- entry/exit from LN = S1PR1 expression
- entry into LN = CCR7, L-selectin, LFA-1

effector T cells:
- Ag activation –> low CCR7 expression –> do not reenter LN or thymus –> circulate through peripheral tissues
- increase expression of various chemokine R’s specific for entry into various tissues