Leukocyte Circulation and Migration into Tissue

CXCL10 (IP-10)

Effector T cell recruitment

Endothelial cells in healthy tissues express adhesion molecules on their surfaces facing the blood. True or False?

False

Integrin Activation

Integrin activation is mediated by chemokine-induced conformational changes in the extracellular domains of the integrins that lead to an increased affinity.

Which cells produce inflammatory chemicals?

Mast cells attached to blood capillary or venule.

Describe how T Cells exit Lymph Nodes?

Naive T cells and Ag-activated T cells have low levels of S1PR1 (Sphingosine-1-phosphate receptor 1) and the cells stay in the LN.. Naïve T cells cannot exit the node for several hours until S1PR1 is re-expressed and the cell exit the LN by mechanism of chemotaxis. S1PR1 is re-expressed after several days and activated and differentiated effector T cells then sense the S1P gradient and exit the node.

CXCL8 (IL-8)

Neutrophil recruitment

CCL2 (MCP-1)

Recruitment of (monocytes)

Addressins

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

Recirculation

is the ability of lymphocytes to repeatedly (1) home to SECONDARY LYMPHOID ORGANS, (2) reside there transiently, and (3) return to the blood.

parenchymal tissues

liver, lungs, kidney

List the Major CC chemokines and function?

CCL2 (MCP-1) CCL19 (MIP-3β) CCL21 (SLC)

Which chemokine (s) is required for the migration of dendritic cells from sites of infection into draining lymph nodes?

CCR7

Important molecules involved in Migration of Naive and Effector T cells

CCR7, CXCR3, CCR5 Function: Activation of interns and chemokinesis.

For Selectins, what is the CD name?

CD62

List the Major CXC chemokines and function?

CXCL8 (IL-8) CXCL10 (IP-10) CXCL12 (SDF-1αβ) CXCL13 (BCA-1)

Activated effector T cells home to sites of infection in peripheral tissues. Cell migration into tissue is mediated by ___________, ___________, ___________, __________.

E-selectin and P-selectin, integrins, and chemokine (CXCL10) that are produced at sites of infection.

Chemokines CCL19 and CCL21 are displayed on the surface of the ______.

High endothelial venule (HEV).

Homing

Homing involves molecules on the surfaces of both the leukocytes (homing receptors and chemokine receptors) and endothelial cells (chemokines).

CXCL12 (SDF-1αβ)

Homing naïve B cells to LNs

Ligand for Leukocytes expressing LFA-1 (lymphocyte function associated antigen-1)

ICAM-1 (CD54) and ICAM-2 (CD102)

Ligand for Monocytes expressing Mac-1 (Macrophage-1 antigen)

ICAM-1 (CD54) and ICAM-2 (CD102)

Maturation of Follicular B lymphocytes

Immature B cells leave the bone marrow through the blood, enter the red pulp of the spleen, and migrate to the periphery of the white pulp. As they mature further, the B cells express the chemokine receptor CXCR5, which promotes their movement into the white pulp in response to a chemokine called CXCL13. Once the maturation is completed within the white pulp, mature naive B cells reenter the circulation and home to lymph nodes and mucosal lymphoid tissues.

Integrin

Integrins mediate tight adhesion of leukocytes with activated endothelium, a critical step in leukocyte migration from blood into tissues.

If one develops an autoimmune disease what does it mean?

It means that their T regulatory cells are not functioning properly.

List the Two very important integrins that are expressed on leukocytes? What are some other important integrins to remember?

LFA-1 (lymphocyte function associated antigen-1) aka CD11aCD18 AND VLA-4 (very late antigen 4) aka CD49dCD29 Other integrins: Mac-1 (Macrophage-1 antigen)

Cytokine Activated Endothelial cells express _________ and _________.

P-selectin (CD62P) and E-selectin (CD62E).

Two types of cells involved in Leukocyte Recruitment?

Selectin and Integrins

E-selectin (CD62E) ligand?

Sialyl Lewis X

P-selectin (CD62P) ligand?

Sialyl Lewis X

L-selectin ligands expressed on HEV is called _______________.

Sialyl Lewis X /peripheral node addressins (PNAd).

CCL19 (MIP-3β)

T cell and dendritic cell migration into parafollicular zones of lymph nodes

CCL21 (SLC)

T cell and dendritic cell migration into parafollicular zones of lymph nodes

Endothelial cells at sites of infection and tissue injury are activated by cytokines secreted by resident immune cells at these sites and express adhesion molecules. What is the consequence of this?

The consequence is INCREASED ADHESIVENESS of the endothelial cells for circulating myeloid leukocytes and Ag-activated (NOT naïve) effector and memory lymphocytes.

Inflammatory Response

The recruitment of leukocytes and plasma proteins from the blood to sites of infection and tissue injury. Inflammation is triggered by recognition of microbes and dead tissues in innate immune responses and is refined and prolonged during adaptive immune responses. Inflammation causes tissue damage.

What is the problem with L-selectin-deficient lymphocytes

They are unable to enter peripheral nodes and "see" the Ag.

Inside out Signaling?

This occurs during integrin activation. It is the process by which intracellular signals, generated in response to chemokines or antigen, alters the binding functions of the extracellular domain of integrins.

The integrins on blood leukocytes are normally in a low-affinity state. True or False?

True

The mechanisms of recruitment of neutrophils (chemokine IL-8) and monocytes (chemokine MCP) is identical except the difference in chemokines involved. True or False?

True

Ligand for Leukocytes expressing VLA-4 (very late antigen 4)

VCAM-1 (CD106)

Ligand for Leukocytes expressing α4β7

VCAM-1(CD106) and MadCAM-1

Leukocyte Recruitment: Rolling

allows chemokine receptors on leukocytes to bind chemokines expressed on endothelium.

Integrin activation occurs in all leukocytes in response to ______________.

chemokine binding to chemokine receptors.

Why is L-selectin important for naive T and B lymphocytes?

important for homing into LNs by interacting with high endothelial venules (HEV).

CC or β chemokines

in which the two defining cysteine residues are adjacent

C chemokines

in which there is a single cysteine

CXC or α chemokines

in which these residues are separated by one amino acid

CX3C chemokines

in which two cysteines are separated by three amino acids.

Leukocyte homing

is cell migration out of the blood and into PERIPHERAL TISSUES, or to a site of an infection or injury.

CD44

is important for the mobilization of effector T cells in sites of infection and inflammation. It can mediate rolling interactions with vascular endothelial cells that express HA, its natural ligand, or even E-selectin (center panel). At these sites, endothelial cells secrete chemokines and express E-and P- selectin and hyaluronic acid (HA). Engagement of CD44 with HA may also trigger GPCR-dependent "inside- out" upregulation of VLA-4-VCAM binding .

Migration or recruitment

is the general process of leukocyte movement from blood into tissues.

L-selectin (CD62L) is not found on endothelial cells like P-selectin and E-selection. It is only expressed on ____________, and binds ligands on endothelial cells.

leukocytes and lymphocytes

Leukocyte Recruitment: Tethering

occurs through transient interactions of selectins and integrin with their ligands.

Leukocyte/lymphocyte HOMING AND RECRUITMENT requires what?

the temporary adhesion of the leukocyte to the endothelial cells of blood vessels.

HEV are present only in ____________.

secondary lymphoid organs.

Chemokines

stimulate leukocyte movement and regulate the migration of leukocytes from the blood to tissues.

Explain Leukocyte Recruitment Generally.

A cascade of adhesive and activation events underlies the trafficking of all subsets of circulating leukocytes which include: Tethering; Rolling; Adhesion; and stop Transmigration in the tissue Migration of leukocytes from blood into tissues involves a series of sequential interactions with endothelial cells, starting with low-affinity leukocyte binding to and rolling along the endothelial surface (mediated by selecting and selection ligands). Next the leukocytes become firmly bound to the endothelium through interactions of leukocyte integrins binding to ligands on the endothelium.

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.

What are unique about B cells and T cells when they enter the Lymph node?

B and T cells migrate to different zones of the LN drawn by chemokines that are produced in these areas.

CXCL13 (BCA-1)

B cell migration into follicles; T follicular helper cell migration into follicles

Naïve lymphocytes enter the lymph node through the _______.

high endothelial venule (HEV).