515 immuno - leukocyte migration (lec 5)

leukocyte migration

Delivery of leukocytes from their sites of maturation (bone marrow or thymus), blood, or peripheral tissues to secondary lymphoid organs

local + systemic

immunity is both ___________

homing

The migration of a leukocyte OUT OF THE BLOOD and into a lymphoid organ, or to a site of an infection or injury

recirculation

The ability of lymphocytes to repeatedly home to secondary lymphoid organs, reside there transiently, and return to the blood. (Like naïve B and T cells)

secondary lymphoid organs

Naive lymphocytes continuously migrate mainly into

primary lymphoid organs + tissues

Memory lymphocytes migrate into

leuokocytes + endothelial cells

The process of leukocyte migration involves molecules on the surfaces of both the

surface molecules

Selectins, Integrins and Chemokines/Chemokine receptors

endothelial cells

when there is an infection or tissue injury, they are activated by cytokines secreted by sentinel cells in the tissues resulting in increased expression of adhesion molecules and chemokines

sentinel cells

DCs, macrophages, and mast cells

selectins + integrins

two classes of adhesion molecules

selectins

plasma membrane carbohydrate-binding adhesion molecules that mediate rolling of circulating leukocytes over endothelial cells

cytokines, histamine, microbial

expression of Selectins and their ligands increases on leukocytes and endothelial cells in response to ________________ products at sites of infection or injury

P- + E-selectins

Endothelial cells express two types of selectins

L-selectin

selectin expressed on leukocytes and not on endothelial cells

sialyl lewis x

these are the ligands that bind to L- selectin, E-selectin and P-selectin are carbohydrates attached to a protein to form complex molecules

glycoproteins

what complex molecules get formed when sialyl lewis x bind to selectins

integrins

cell surface proteins that mediate adhesion (full stops) of cells to other cells or to extracellular matrix, through specific binding interactions with various ligands

extracellular heads

structures of the integrin that contribute to ligand binding

cytoplasmic domains

structures of the integrin that contribute to interacting with cytoskeletal components

LFA-1 + VLA-4

two important integrins are expressed on leukocytes

1CAM-1

ligand for LFA-1 and is expressed on ENDOTHELIAL cells; also lymphocytes, DCs, macrophages, fibroblasts, and most epithelial cells

VCAM-1

ligand for VLA-4 and is expressed on ENDOTHELIAL cells

Mac-1

an integrin that is expressed on the majority of myeloid cells and binds to ICAM-1 and mediates adhesion to endothelium

CD103

integrin that binds to an epithelial adhesion molecule called E-cadherin; expressed on subsets of T cells and DCs

a4B7

an integrin that is expressed mostly on lymphocytes that home to intestinal mucosa; binds to an endothelial protein called MadCAM-1

bent

integrins are in a low-affinity state when they are not bound to their ligand

extend

integrins are in a high-affinity state when they are bound to their ligand

chemokines

what brings ligands to integrins??

chemokines

large family of cytokines that stimulate leukocyte movement and regulate the migration of leukocytes from the blood to lymphoid organs and tissues

CC and CXC

four major families of chemokines

2 cysteine residues

CC subfamily characteristics

amino acid separation

CXC subfamily characteristics

fibroblasts + endo + epithelial cells

chemokines of the CC and CXC subfamilies, aside from leukocytes, are produced by several types of tissue cells, such as _____________

GPCRs

receptors for chemokines belong to

cytoskeletal changes

G proteins stimulate signaling events that result in ______ resulting in increased cell motility, survival and proinflammatory responses

leukocytes

Chemokine receptors are mainly expressed on the surface of

chemotaxis

chemokines stimulate movement of leukocytes along the concentration gradient of the secreted chemokine toward its source (Chemotactic gradient). Thus, leukocytes migrate toward infected and damaged cells in tissues, where chemokines are produced

homeostatic chemokines

regulate the traffic of lymphocytes and other leukocytes through different regions of secondary lymphoid organs; expressed constitutively at those sites and maintain normal lymphoid tissue architecture

CCR7

DCs migration depends on expression of this chemokine receptor and is induced when they encounter the microbes in question; Naive T cells also express this, which explains how DCs and naive T cells localize to the same place in lymph nodes

selectin-mediated

tethering + rolling

chemokine-mediated

integrin activation

integrin-mediated

stable adhesion

cytoskeleton-driven

transmigration/diapedesis

margination

At sites of inflamed tissues, blood vessels dilate, and blood flow slows. As a result, leukocytes, being larger than red blood cells, tend to move away from the central axial flow and closer to the vessel lining

diapedesis

Leukocytes usually transmigrate between the borders of endothelial cells to reach extravascular tissues

VE-cadherin complex

diapedesis requires a transient and reversible disruption of junction proteins that hold endothelial cells together

neutrophils

the first type of leukocyte to be recruited from the blood into a site of infection or tissue injury

monocytes

follows hours later and continues, perhaps for days, after neutrophil recruitment stops

CXCR1 + R2

Neutrophils express this subfamily of chemokines

CCR2

monocytes express this subfamily of chemokines

CXCL8

Early neutrophil recruitment is a consequence of early and abundant ______ production by tissue resident macrophages in response to infections

clonal expansion

lymphocytes that have recognized and become activated by antigen within secondary lymphoid organs proliferate and differentiate to produce thousands of effector and memory cells

CCR7

naive T cell migration out of the blood through the HEVs into the lymph node stroma involves the adhesion molecules L-selectin and LFA-1 and the ______ receptor

CCL19 + 21

The principal chemokines involved in leukocyte homing to T cell zones of lymphoid tissues

FRCs

The main source of CCL19 and CCL21 is forming the conduits within the T cell zone, and CCL21 is also constitutively produced by HEVs

S1P

exit of T cells from lymph nodes is dependent on a lipid chemoattractant called

S1PR1

S1P binds to a receptor on T cells called

inverse

There is an _____ correlation between the expression of S1PR1 and the concentration of S1P in the environment

blood + lymph

S1P is present at higher concentrations in the

naive

when T cells are ____, S1PR1 is expressed

activated

when T cells are ____, S1PR1 is supressed

CXCR3

during differentiation of naive into effector lymphocytes, T cells lose expression of CCR7 and start expressing receptor

CXCL10

CXCR3’s needed chemokine for binding

L-selectin

during T cell differentiation, the stop expressing the selectin

CCR7, CXCR4 + 5

Homing of naive B cells from the blood into lymph nodes depend on these chemokine receptors

plasmablasts

some activated B cells that are generated in secondary lymphoid organs and are committed to secreting antibodies will differentiate into migratory cells

long lived plasma cells

Plasmablasts enter the circulation and migrate into bone marrow or tissues where they further differentiate into plasma cells and secrete antibodies for long periods