Leukocyte Migration- Lecture 3

Question 1

What is the definition of Migration/Recruitment/Leukocyte homing?

Answer 1

Leukocytes from blood Tissue (used to fight and respond to infection)

Question 2

What is the definition of recirculation?

Answer 2

LYMPHOCYTES moving from blood back to secondary lymph tissue (naïve) in order to look for antigen

Question 3

What are chemokines?

Answer 3

Types of cytokines that regulate movement of leukocytes

Question 4

How do families of chemokines differ?

Answer 4

Because of the number and location of N-terminal Cysteine residues

Question 5

What is the role of chemokine CCL2/MCP-1?

Answer 5

Monocyte recruitment

Question 6

What is the role of chemokine CCL19/MIP-3ß?

Answer 6

T cell/Dendritic Cell migration into LN

Question 7

What is the role of chemokine CCL21/SLC?

Answer 7

T cell migration into LN

Question 8

What is the role of chemokine CXCL8?***

AKA IL-8

Answer 8

Neutrophil recruitment

Question 9

What is the role of chemokine CXCL10?

Answer 9

Effector T cell recruitment

Question 10

what is the role of chemokine CXCL12?

Answer 10

Naive B cells to LN (homing)

Question 11

What is the role of chemokine CXCL13?

Answer 11

B cell migration to follicles

Question 12

What are the 6 steps of leukocyte migration?

Answer 12

1. Infection/Inflammation
2. Activation of Endothelium
3. Tethering (Selectins)
4. Rolling (Integrins/Inside-out signaling)
5. Adhesion and stop
6. Transmigration into tissue

Question 13

Neutrophils/monocytes start in _____ and can enter and circulate through the blood

Answer 13

Bone marrow

Question 14

Do Neutrophils need to be activated to leave bone marrow and enter blood circulation

Answer 14

No they do not

Question 15

When do neutrophils enter the tissues and how do they enter?

Answer 15

When infection/inflammation is detected

Neutrophils leave the blood and enter tissues through POST CAPILLARY VENULES

In liver, lungs, and kidney they enter via capillaries

Question 16

Neutrophils and monocytes are activated by _______ or _______

Answer 16

Pathogen

Inflammation

Question 17

Once neutrophils are activated, what do they produce and why?

Answer 17

Neutrophils produce IL-1 to recruit other leukocytes/lymphocytes

Question 18

During the second stage of leukocyte migration, healthy tissues that originally do not have selectins present on the epithelium begin to express selectins. Why?

Answer 18

Cytokines released during infection/inflammation activate the expression of selectins on endothelium.

*Note that selectins can also be found on leukocytes/lymphocytes, but they are not activated by cytokines.

Question 19

What are the 3 selectins and where are they found?

Answer 19

P-selectin –> On endothelium
E-selectin –> On endothelium

L-selectin –> On leukocytes/lymphocytes

Question 20

What activates P-selectin?

Answer 20

Activated by Histamine/thrombin`

Question 21

What activates E-selectin?

Answer 21

TNF and IL-1

Question 22

What do E-selectin and P-selectin bind to once activated?

Answer 22

Xialyl Lewis X on lymphocytes/leukocytes

Question 23

What activates L-selectin and what does it bind to?

Answer 23

L-selectin is not activated by anything, therefore it is always active

Binds to PNAD (peripheral node addressins) on HEV on endthelium

Question 24

What is the purpose of step 3 of leukocyte migration, tethering of the selectins?

Answer 24

NECESSARY to slow down leukocytes to initiate rolling

Question 25

What carries out step 4 of leukocyte migration, rolling?

Answer 25

Integrins by mediating adhesion of leukocytes to the endothelium

Question 26

Where are integrins found?

Answer 26

On leukocytes and they bind to the endothelium

Question 27

What are the ligands that these integrins bind to? (remember that the integrins are found on leukocytes, so their ligands will be found on the endothelium) LFA1? MAC1? VLA4? A4ß7?

Answer 27

LFA1: ICAM MAC1: ICAM VLA4: VCAM1 A4ß7: VCAM1 and MadCAM1 (Molecular Addressin Cell Adhesion Molecule)

Question 28

Integrins on leukocytes in blood without chemokines= _____

Answer 28

Weak affinity

Question 29

Integrins on leukocytes in blood with chemokines= _______. Why?

Answer 29

High affinity *due to chemokines from the injured/infected site of endothelium

Question 30

NAIVE CELLS= __ _____ _____= __ _____

Answer 30

NAIVE CELLS= NO CHEMOKINE RECEPTORS= NO ROLLING

Question 31

ACTIVATED CELLS will have _____ ______

Answer 31

Chemokine receptors

Question 32

Integrins bind to ligands on_____ with high affinity

Answer 32

Endothelium

Question 33

When integrins bind to the ligands what happens?

Answer 33

Stops leukocytes from rolling

Question 34

In what way is T cell migration in tissues different from leukocytes?

Answer 34

Rolling is mediated by hyaluronic acid on T cell binding to CD44 on the endothelium. When these bind, VLA4/VCAM integrin binding increases and EFFECTOR T cells mobilize.

Question 35

What is another name for transmigration into tissues?

Answer 35

Diapedesis

Question 36

What occurs during the 6th stage of leukocyte migration "diapedesis/transmigration into tissues"?

Answer 36

Cells slide through gap junctions and openings between endothelial cells to leave the blood and enter the tissue with an “amoeboid” shape. Leukocytes then migrate towards site of infection based on more chemokines being released by cells already at infection site.

Question 37

Explain what happens during migration of naive B cells and lymphocytes.

Answer 37

Enter LN via HEV Have L-Selectins on them -Bind to PNADS on HEV -CCR7 (on T cells) bind to CCL19/21 (HEV) to activate integrins on HEV

Question 38

Explain what happens during recirculation of B cells and lymphocytes when antigens are not found and when they are found.

Answer 38

No Ag is found --> B and T cells returns to lymph (efferent lymph vessel) and enters other secondary lymph organs --> eventually reaches thoracic duct and is returned to IVC Ag is found and B/T cell is activated --> B/T cell returns to circulation. Goes through tethering/rolling/adhesion process until it enters tissue where Ag came from. *Note that T cells bind to CXCL10.

Question 39

Where do B and T cells enter LN's?

Answer 39

HEV

Question 40

How are B and T cells separated in the lymph node?

Answer 40

CXCR5 (on B cells) binds to CXCL13 (secreted from primary follicle). In spleen enter the red pulp and migrate to where CXCL13 Is secreted from (white pulp). Immature to mature and then reentry into circulation. *Note that in primary follicles B cells can find their antigen and proliferate to form secondary follicles CCR7 (on T cell) binds to CCL21 in T cell zone

Question 41

Explain the pathway of the T cell from entry to exit of the LN in terms of S1P.

Answer 41

In the blood S1P (a blood homing protein) binds to S1PR1 (receptor on T cells), which allows for T cell entry into the LN. Binding causes internalization of S1PR1, which means S1P can no longer be sensed. Reexpression of S1PR1 allows S1P to bind, leading to the T cell exiting the LN.