Lecture 3: Leukocyte Circulation and Migration into Tissue

Question 1

Recirculation is the ability of lymphocytes to repeatedly

Answer 1

• Home to secondary lymphoid organs
• Reside there transiently
• return to the blood

Question 2

Inflammation is triggered by recognition of ___ and ____ in _____ immune responses and refined and prolonged during _____ immune responses

Answer 2

Inflammation is triggered by recognition of microbes and dead tissues in innate immune responses and is refined and prolonged during adaptive immune responses

Question 3

A cascade of adhesive and activation events underlies the trafficking of all subsets of circulating leukocytes which include:

Answer 3

• Tethering
  
  • Occurs through transient interactions of selectins and integrin with their ligand
• Rolling
  
  • allows chemokine receptors on leukocytes to bind chemokines expressed on endothelium
• Adhesion and Stop
  
  • Receptors signal and activate integrins on leukocytes which interact wiht ligands expressed on endothelium and trigger adhesion to the endothelium
• Transmigration in the tissue
  
  • Leukocytes transmigrate into extravascular space where they can migrate down chemokine gradients toward specific areas

Question 4

Do healthy endothelial cells epxress adhesion molcules on their surfaces

Answer 4

No (endothelial cells at sites of infection and tissue injury are activated by cytokines secreted by resident immune cells at these sites, which leads to adhesion molecule expression)

Question 6

_____ comprise a set of several adhesion molecules on the surface fo the endothelial cells

Answer 6

Addressins

Question 7

____ are plasma membrane carbohydrate-binding adhesion molecules that mediate an initial step of low-affinity adhesion of circulating leukocytes to endothelial cells lining post-capillary venules

Answer 7

Selectins (Note similar to C-type lectins becuae they bind carbohydrates)

Question 8

Selectins are expressed on

Answer 8

• Leukocytes
  
  • L-Selectin (CD62L)
• Endothelial cells
  
  • P-selectin (CD62P)
    
    • moves to lumenal surface in response to histamine and thrombin
  • E-selectin (CD62E)
    
    • Synthesized and expressed on the endothelial cell surface within 1 to 2 hours in response to the cytokines
      
      • IL-1
      • TNF
      • (note that microbial products such as LPS can also stimulate its expression)

Question 9

Ligands for P-selectin (CD62P)

Answer 9

• Sialy Lewis X on PSGL-1 and other glycoproteins
• Neutrophils, monocytes, and T cells (effector, memory)

Question 10

Ligands for E-selectin (CD62E)

Answer 10

• Silayl Lewis X (e.g., CLA-1) on glycoproteins
• Nuetorphils, monocytes, T cells (effector, memory)

Question 11

Ligands on L-selectin (CD62L)

Answer 11

• Sialyl Lewis X/PNAd on GlyCAM-1, CD34, MadCAM-1, other; endothelium (HEV)

Question 12

____ are heterodimeric cell surface proteins composed of tow noncovalently linked polypeptide chains that mediate adhesion of cells to other cells or to extracellular matrix, through specific binding interactions with various ligands

Answer 12

Integrins

Question 13

There are more than 30 different integrins, all with the same basic structure, containing

Answer 13

one of more than 15 types of alpha chains and one of seven types of beta chains

Question 14

What are the two important integrins expressed on leukocytes

Answer 14

• LFA-1 (leukocyte function-associated antigen 1)(CD11aCD18)
• VLA-4 (very late antigen 4) (CD49dCD29)

Question 15

The extracellular portion of ICAM-1 is composed of globular domains, called ______, which share a sequence homology and structural features with domains foudn in Ig molecules

Answer 15

immunoglobulin (Ig) domains

Question 16

Ligands for LFA-1 (CD11aCD18)

Answer 16

• ICAM-1 (CD54)
• ICAM-2 (CD102)
• ICAM-3 (CD50)

Question 17

Ligands for Mac-1 ( CD11bCD18)

Answer 17

• ICAM-1 (CD54)
• ICAM-2 (CD102)

Question 18

Mac-1 (CD11bCD18) is an integrin found on

Answer 18

• Neutrophils
• Monocytes
• Dendritic cells

Question 19

L-selectin (CD62L) ligand expressed on HEV is called

Answer 19

• Peripheral node addressin (PNAd)

Question 20

VLA-4 (CD49aCD29) is an integrin found on

Answer 20

• Monocytes
• T cells (naive, effector, memory)

Question 21

Where is the integrin Alpha₄Beta₇ distributed

Answer 21

• Monocytes
• T cells (gut homing, naive, effector, memory)
• B cells (gut homing)

Question 22

What is the ligand for integrin Alpha4Beta7

Answer 22

• VCAM-1 (CD106)
• MadCAM-1
• endothelium in gut and gut-associated lymphoid tissues

Question 23

The term integrin comes from the function of these proteins, which is

Answer 23

• Integrate signals triggered by extracellular ligands with cytoskeleton-dependent motility, shape change, and phagocytic responses

Question 24

Integrin are able to resond to intracellular signals by

Answer 24

• increasing their affinity (integrin activation)
• Integrin activation occurs in all leukocytes in response to chemokine binding to cehmokine receptors

Question 25

In T lymphocytes integrin activation occurs for formation of the immunological synapse when antigen binds to ____

Answer 25

TCRs

Question 26

integrins on blood luekocytes are normally in a ___-affinity state

Answer 26

low

Question 27

There are about ___ human chemokines, which are classified into four families on the basis of the number and location of N-terminal cysteine residues, what are the families

Answer 27

• 50
• C cehmokines
  
  • in which there is a single cysteine
• CC chemokines (beta chemokines)
  
  • in which the two defining cysteine residues are adjacent
• CXC (alpha chemokines)
  
  • in which the two cysteine residues are separated by one amino acid
• CX₃C chemokines
  
  • in which two cysteines are separated by three amino acids

Question 28

Neutorphils and monocytes enter the tissue though post-capillary venules except _________ (_______) where all blood cells enter though capillaries

Answer 28

parenchymal tissues (liver, lungs, kidney)

Question 29

Activated resident macrophages produce cytokines ____ and )))) that induce the rapid induction of expression of pre-formed P-selectin on the surface of enothelial cells

Answer 29

• TNF and IL-1

Question 30

The interaction between P-selectin and ligands on leukocytes initiates ___ on the endothelium, which is further stabilized by L-selctin binding to ligands on enothelial cells

Answer 30

rolling

Question 31

After rolling has been initiated enothelial cells present a chemokine _______ that is recognized by receptors on neutrophils and ___ on monoctyes

Answer 31

• IL-8 (CXCL8) for neutrophils
• MCP-1 (CCL2)

Question 32

L-selectin ligands expressed on HEV have been collectively called

Answer 32

peripheral node addressins (PNAd)

Question 33

What chemokines are expressed on the surface of the HEV. and them binding to ____ activates integrins

Answer 33

• CCL19 and CCL21
• CCR7

Question 34

Naive T cells have low levels of ____ because the receptor is internalized after binding S1P in the blood. Naive T cells that have recenlty entered a LN cannot sense S1P concentration gradient between the T cell zone of the node and the lymph. Naive T cells cannot exit the node for several hours until _____ is re-expressed and the cell exit the LN by mechanism of chemotaxis. If The T cell is activated by an anitgen then the _____ re-expression takes several days tthus allowing for clonal expansion to occur before the T cell leaves the Lymph node

Answer 34

• S1PR1 (spingosine 1-phosphate receptor 1)
• S1PR1
• S1PR1

Question 35

CD44 can mediate rolling interactions with vascular endothelial cells that express ___, its natural ligand, or even _______

Answer 35

• Hyaluronic acid​
• E-Selectin

Question 36

Engagement of CD44 with HA may rigger GPCR-dependent upregulation of

Answer 36

VLA-4 to VCAM binding

Question 38

As they mature, B cells express the chemokine receptor _____, which promotes their movement into the white pulp in response to a chemokine called ____

Answer 38

CXCR5, CXCL13

Question 39

Homing of B cells to lymph nodes require chemokine of ______ and _____ on HEV and their chemokine receptors _____ and ____ on naive B cells

Answer 39

• CXCL12 and CCL19/CCL21
• CXCR4 and CCR7

Question 40

IN the stroma of the lymph nodes, B cells migrate into follicles driven by _____ recognized by _____ expressed on naive B cells

Answer 40

• CXCL13
• CXCR5