Lecture 8

Question 1

Different Sites, Similar Mechanisms of Trafficking:

Post- capillary venule

Answer 1

neutrophils and monoytes migrate to sites of infection and tissue injury: inflammation

Question 2

Different Sites, Similar Mechanisms of Trafficking:

Lymph node

Answer 2

Naieve T and B cellsmigrate into secondary lymphoid organs

come in via High Endothelial Venule

Question 3

Different Sites, Similar Mechanisms of Trafficking:

Post Capillary Venule pt 2

Answer 3

Effector and Memory T cells migrate into sites of infection and tissue injury:
CELL-MEDIATED IMMUNITY

Question 4

Individual lymphatic vessels merge into…

Answer 4

Individual lymphatic vessels merge into larger afferent lymphatic vessels that transport the antigens and antigen-bearing dendritic cells to the lymph nodes

Question 5

What are the Effects of Antigen Capture and Transport

Answer 5

1. Naïve T cells and B cells test their antigen receptors against the antigen that has been transported there and concentrated from the peripheral tissue.
2. Activated/Effector T cells may leave the lymph node via the efferent lymphatic vessel and travel to the infected tissue via the lymph and blood.

Question 6

Skin resident Dendritic cell…

Answer 6

Langerhan’s Cells

really good at phagocytosis and draining into the lymph!

The epithelial tissues of the body contain a network of resident immature dendritic cells, that capture antigen and transport it to the regional draining lymph nodes

Question 7

______________________ makes sure that ___________& ________ cells go to the right place in the lymph node

Answer 7

Chemokines make sure that B and T cells go to the right place in the lymph node

Question 8

Plasmacytoid Dendritic Cells

Answer 8

VIRUS PRESENTER

1. Major Function:
   Antiviral immunity: early innate response; priming of antiviral T cells

Cytokines produced
TYPE 1 INF

Question 9

Major Cytokines produced in Plasmacytoid Dendritic Cells

Answer 9

TYPE 1 INF

VIRUS

Question 10

Toll like receptors on Plasmacytoid Dendritic Cells

Answer 10

TLR 7

TLR 9

Question 11

HoW do antigen-bearing DCs leave the peripheral tissue and migrate to the draining LYMPH nODES?

(Slide 13)

Answer 11

1. Immature DCs first must be “activated” in the peripheral tissues by invading microbes or inflammatory cytokines.
2. Immature DCs are activated when:

A) DC TLRs bind to microbial components,

B) DC is stimulated by inflammatory cytokines induced by the microbe.

Question 12

Pro-inflam cytokines

Answer 12

IL-1

TNF-alpha

Question 13

Co-stimulatory molecule B7-1 & B7-2 works with….

slide 13

Answer 13

CD28 on T cells to co-stim and present antigen

Question 14

What changes in a dendritic cell to change it from a cell that does antigen uptake—–to a cell that must focus on PRESENTING antigen?

Answer 14

SIGNAL 1. Increases MHC/antigen complexes: provide 1 of 2 signals T cells need to become activated.

SIGNAL 2. Increases costimulatory molecules: provide the second that T cells require to become activated.
(ex B7-1 & B7-2 increase the binding strength)

Question 15

What is the result of binding pro inflam cytokines

Answer 15

NF-kappa B is upregulated

&

transcription factors are expressed via the pathway

& the co-stimulatory molecules will be made and placed on the dendritic cell

Question 16

What is the role of CCR7?

slide 15

Answer 16

1. Activated DCs increase expression of CCR7, that binds the CCL19 and CCL21, produced in the T cell zones of the lymph node.
2. These chemokines direct the activated DCs to exit the peripheral tissue and migrate through the lymphatic vessels to the T cell zones of the lymph nodes.

Question 17

ccr& MEANS….

Answer 17

CHEMO KINE receptor looking for a ligand

Question 18

The anatomical distribution of T and B cells within the lymph nodes is also due to effects of chemokines.

please explain

Answer 18

1. Naïve T cells also express CCR7, which binds CCL19 and CCL21 produced in the T cell zone (paracortex).
2. T cell and DC expression of CCR7 assures the antigen presenting DCs and T cells will come together in the LNs.

Question 19

How do B -cells get to the follicles in the lymph nodes?

Answer 19

Naïve B cells express CXCR5, which binds to the CXCL13, produced only in the follicles (by the follicular dendritic cells), thus directing the B cells to this site.

Question 20

lymphocyte recirculation

Answer 20

Naïve lymphocytes are constantly circulating from the blood, into through the lymphatics and LNs, and back to the blood stream…

Lymphocyte recirculation, enables the limited number of naïve lymphocytes that are specific for a particular foreign antigen to search for that antigen throughout the body.

Most T cells pass through each LN at least once a day!

Question 21

How would you expect this recirculation pattern to change once a lymphocyte has been activated by antigen?

Answer 21

lymphocyte homing.

1. The process by which particular lymphocytes selectively enter lymph nodes or some tissues, but not others, is called lymphocyte homing
2. Once activated, effector lymphocytes no longer preferentially traffic to the lymph nodes, rather they must instead find their way to the site of infection

Question 22

lymphocyte homing.

Answer 22

The process by which particular lymphocytes selectively enter lymph nodes or some tissues, but not others, is called lymphocyte homing

Question 23

What causes the patterns of circulation to change for naïve vs effector Lymphocytes?

Answer 23

Chemokines and Adhesion molecules

think about the images

Question 24

HEVs are….

Answer 24

High Endothelial Venules (HEV) –HEVs are rich in adhesion molecules and chemokines for naïve T lymphocytes

Question 25

T cell homing to LNs is similar to PMN migration into inflamed tissue……please explain this process

IMPORTANT!
(Slide 24 and 25)

Answer 25

1. Naïve T cells express a receptor called L-selectin (CD62L) that binds to carbohydrate ligands expressed only on the endothelial cells lining the HEV (PNAd) and induces rolling
2. The chemokines produced by the T cell zones of the LN (CCL19 and CCL21), bind to CCR7 and cause high affinity integrins (LFA-1 and VLA-4) to be expressed, causing the naïve T cells to bind strongly to intercellular adhesion molecule 1 (ICAM-1) on the HEV……resulting in firm adhesion and migration into the T zone of the LN stroma.

Question 26

(PNAd)

Answer 26

carbohydrate ligands expressed only on the endothelial cells lining the HEV (PNAd) and induces rolling

Question 27

CD62L

slow ya roll!

Answer 27

Naïve T cells express a receptor called L-selectin (CD62L)—-Caues the slow and roll

Question 28

how does a t-cell get out???

(think of the timer!!)

chemotactic gradients at different parts of the lymph node

Answer 28

S1P and S1P1 receptors

(S1P R (receptor)

if the antigen is in the lymph nodes then there is a delay in S1P1 Receptor so that the cell can do clonal expansion and grow. eventually will leave via the S1P antigen levels being high at the exit sites

if there is NO antigen then the S1P-R will build up and there is a LOT on S1P antigen by the EXIT!!!!

Question 29

CLA-1

Answer 29

For example: T cells that traffic to the skin express high levels of a particular ligand for E selectin called CLA-1, and chemokine receptors, which bind to chemokines commonly expressed by inflamed skin.

Question 30

Clinical Correlate:

What is a mechnism for treatment of M.S and IBS?

these are both auto-immune diseases

Answer 30

Engineered Abs against integrins or endothelial adhesion molecules are effective drugs which block migration of effector T cells into tissues in diseases such as multiple sclerosis and inflammatory bowel disease.

good treatment against auto immune disease where T-cells are attacking self

Question 31

Fingolimod is a drug used to treat autoimmune diseases, which blocks the function of sphingosine-1 phosphate (S1P), by binding to its receptor S1PR1 and downregulating it’s expression. Patients treated with this drug become lymphopenic, ie, they have low number of lymphocytes in the blood. Why?

Answer 31

S1P binding to S1PR1 on lymphocytes is required for exit of lymphocytes from lymphoid tissues

Question 32

A group of researchers is studying the effects of the CXCL13 gene by knockout mice experiments. Which of the following might you expect to see upon examination of the animal’s lymph nodes

Answer 32

Hypocellular follicles

Question 33

A group of researchers is studying the effects of the CXCL19/21 gene by knockout mice experiments. Which of the following might you expect to see upon examination of the animal’s lymph nodes

Answer 33

Hypocellular paracortex