Leukocyte Circulation and Migration into Tissue Flashcards by Colt Moller

migration or recruitment is the general process of leukocytes

movement from blood into tissues

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recirculation is the ability of lymphocytes to repeatedly:

home to secondary lymphoid organs
reside in secondary lymphoid organs transiently
return to the blood

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leukocyte homing is

cell migration out of the blood and into peripheral tissues. mostly occurs in response to an infection or tissue injury

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the recruitment of leukocytes and plasma proteins from the blood to sites of infections and tissue injury is a major part of the process of

inflammation

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inflammation is triggered by

recognition of microbes and dead/injured tissues in innate immune responses and is refined and prolonged during adaptive immune responses

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neutrophils and monocytes arise in the

bone marrow and circulate in the blood

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neutrophils and monocytes are ready to be recruited into tissues sites of infection and injury with or without activation

without activation

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neutrophils and monocytes enter the tissue through _____ except parenchymal tissues (liver, lungs, kidneys) where all blood cells enter through _____

post-capillary venules

capillaries

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functions of myeloid leukocytes

eliminate infectious pathogens

clear dead tissues

repair the damage

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leukocyte recruitment: a cascade of adhesive and activation events underlies the trafficking of all subsets of of circulating leukocytes including:

tethering: transient interactions of selectins and integrins with their ligands
rolling: chemokine receptors on leukocytes to bind chemokine expressed on endothelium
adhesion and arrest: receptors signal and activate integrins on leukocytes which interact with ligands on endothelium and trigger adhesion/arrest to the endothelium
transmigration into the tissue: leukocytes then transmigrate into the extravascular space where they follow chemokine gradients towards areas of infection and/or tissue damage

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once leukocytes have completed trans-endothelial migration, they

interact with chemokines in the underlying basement membrane

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following diapedesis, cells adopt _____ shape

an amoeboid

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transmigration of leukocyte:

capture and rolling of cells involves

selectins

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transmigration of leukocytes:

activation (rolling -> adhesion) involves

chemokines

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transmigration of leukocytes:

firm adhesion involves

adhesion molecules

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after diapedesis, leukocytes migrates in a polarized fashion along

collagen fibrils in response to a chemotactic gradient toward the site of infection/inflammation

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chemotactic receptors are located where on the migrating leukocyte

on the leading edge

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endothelial cells in _____ tissues do not express adhesion molecules on their surfaces facing the blood

healthy

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tissue recruitment of immune cells:

endothelial cells at sites of infection and/or tissue injury

are activated by cytokines locally secreted by resident immune cells (mast cells and macrophages)
express adhesion molecules

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tissue recruitment of immune cells:

the consequence of activated endothelial cells is the increased adhesiveness for circulating _____ and _____

leukocytes (neutrophils, monocytes, basophils, and eosinophils)

antigen-activated (not naive) lymphocytes (T and B cells)

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tissue recruitment of immune cells:

leukocyte/lymphocyte homing/recruitment requires the temporary

adhesion of the leukocyte/lymphocyte to the endothelial cells of blood vessels

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homing involves molecules on the surfaces of both the _____ and _____

leukocyte/lymphocyte (homing receptors and chemokine receptors)

endothelial cells (chemokines)

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addressins comprise a set of adhesion molecules expressed only on the surface of

high endothelial venules (HEV)

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selectins provide _____ interactions with their ligands

low affinity

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the selectins (E and P selectins) are a family of glycoproteins that mediate low-affinity endothelial-leukocyte interactions, thus promoting the

tethering and rolling of leukocytes through interactions with specific ligands on leukocytes

only ____ endothelial cells express P-selectin and E-selectin

activated

P-selectin is pre-synthesized by

unactivated endothelial cells and stored in granules which promptly move to the surface in activated endothelial cells

when is E-selectin is synthesized and expressed on the endothelial cell surface

within 1-2 hours in responses to histamine, thrombin, and inflammatory cytokines (IL-1 and TNF) produced by mast cells and tissue macrophages in response to infection/tissue injury

the ligands for E-selectin and P-selectin are ______ on innate immune cells (neutrophils, monocytes, eosinophils, and basophils) as a complex sialylated carbohydrates related to the ______

constitutively expressed Lewis X antigen

L-selectin is most important for

homing of naive T and B lymphocytes into lymph nodes by interacting with HEV but it also has an accessory function in inflammation

L-selectin ligands expressed on HEV is called

peripheral node addressins (PNAd)

integrins provide a ____ affinity interaction with their ligands

high

functions of integrins

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

there are more than _____ different integrins, all with the same basic structure

integrins mediate _____ of cells to other cells or to extracellular matrix via various specific ligands

adhesion

all leukocytes, including B and T cells, monocytes, macrophages, neutrophils, basophils, and eosinophils express the integrin _____

lymphocyte function-associated antigen 1 (LFA-1)

integrin Lymphocyte function-associated antigen 1 (LFA-1) binds its ligand _____ and _____, which is expressed on _____

ICAM-1 ICAM-2 cytokine-activated endothelial cells

leukocytes also express integrin Very Late Antigen-4 that binds to _____, which is expressed on _____

VCAM-1 cytokine-activated endothelial cells

integrin alpha4beta7 binds to _____ and ______ which are found on _____

VCAM-1 and MadCAM endothelium in gut and associated lymphoid tissue

integrin Mac-1 binds to ligand _____ and _____ on _____

ICAM-1 ICAM-2 cytokine-activated endothelial cells

integrins are able to respond to intracellular signals by rapidly increasing their affinity (integrin activation), this occurs in all leukocytes in response to

chemokine binding to chemokine receptors

integrin activation is mediated by chemokine-induced conformational changes in the extracellular domains of the integrins that lead to

an increased affinity

signaling involved in integrin activation

inside-out signaling

the integrins on blood leukocytes are normally in a _____ state

low-affinity

when rolling of leukocytes occurs, chemokines displayed on the endothelial surface can bind

chemokine receptors on the leukocyte

chemokine receptor signaling occurs, which

activates integrins of leukocytes, increasing their affinity for their ligands on the endothelial cells

bent conformation of leukocyte integrin

low-affinity

extended conformation of leukocyte integrin

high-affinity

chemokines are a large family of structurally _____ cytokines

homologous

the name chemokine is a contraction of

CHEMOtactic and cytoKINE

chemokines stimulate leukocyte _____ and regulate the _____ of leukocytes from the blood to tissue

movement migration

C chemokines

single cysteine

CC or Beta chemokines

2 defining cysteine residues are adjacent

CXC or alpha chemokines

cysteine residues are separated by amino acid

CX3C chemokines

2 cysteines are separated by 3 amino acids

MALT

mucosa-associated lymphoid tissue (gut)

42 percent of all lymphocytes at a given point in time are found

in the lymph nodes and stay there on average about 12 hours

45 percent of all lymphocytes at a given point in time are found

in the spleen and stay there on average about 5 hours

lymphocytes are in circulation roughly ____ min

10 percent of all lymphocytes at a given point in time are found

in the MALT

naive T cells preferentially leave the blood and enter

lymph nodes across the HEV

dendritic cells bearing antigen enter the lymph nodes through

afferent lymphatic vessels

if T cells recognize their antigen, they are activated, and

return into circulation leaving the LN via efferent lymphatic vessels

effector and memory T cells preferentially leave the blood and enter peripheral tissues through

venules at sites of inflammation

unlike E and P selectins which are expressed on activated endothelial cells, L-selectin is

strongly and constitutively expressed by naive T and B lymphocytes

L-selectin deficient lymphocytes are unable to

enter peripheral nodes and "see" the antigen

naive lymphocytes enter the lymph nodes through the _____ which express ______

HEV selective Ligands for L-selectin

L-selectin ligands expressed on HEV have been collectively called _____

peripheral node addressins (PNAd)

lymphocytes that did not find their antigen leave the lymph nodes via

efferent lymphatics and enter downstream lymph nodes

P-selectin is expressed where

on activated endothelium

ligand for P-selectin is expressed

constitutively on innate immune cells (neutrophils, monocytes, eosinophils, and basophils; and on activated lymphocytes as a complex sialylated carbohydrates related to the Lewis X antigen

ligand for E-selectin is expressed

constitutively on innate immune cells (neutrophils, monocytes, eosinophils, and basophils; and on activated lymphocytes as a complex sialylated carbohydrates related to the Lewis X antigen

E-selected is expressed

on activated endothelium

L-selectin is expressed

mostly on lymphocytes

ligands for L-selectin is expressed

on HEV and is called peripheral node addressins (PNAs)

what cells express Mac-1 integrin

neutrophils, monocytes, DCs

what cells express alpha4beta7 integrin

monocytes, T cells (gut homing, naive, effector, memory), B cells (gut homing)

naive lymphocytes enter the LN through an artery, leaving the circulation by moving across the wall of the

HEV

Ag-loaded DCs enter the LN through

afferent lymphatic vessels coming from the site of Ag entry

Ag-loaded DCs migrate where in the LN

to the T cell-rich areas

naive T/B cells that didn't find their Ags in the LNs leave it via

efferent lymphatic vessel to migrate to other LNs without entering the circulation

chemokines CCL19 and CCL21 are displayed on the surface of

HEV

chemokines CCL19 and CCL21 bind to chemoreceptors ______ and activates integrins

CCR7

chemokine CXCL8 original name major function

IL-8 neutrophil recruitment

chemokine CCL2 original name major function

MCP-1 mixed leukocyte recruitment (monocytes)

chemokine CCL19 original name major function

MIP-3beta T cell and DC migration into parafollicular zones (T-cell zone) of lymph nodes

chemokine CCL21 original name major function

SLC T cell and DC migration into parafollicular zones (T-cell zone) of lymph nodes

naive T cells spend approx _______ surveying a LN for specific Ag and if undetected, they transmigrate into cortical or medullary sinuses and exit through ______

6-12 hours efferent LV

naive T cells express low levels of ______ because the receptor is internalized after binding _____ which has high concentration in the blood

S1PR1 S1P

naive T cells that have recently entered a LN cannot sense the S1P concentration gradient between the T cell zone of the lymph node and the lymph and therefore do NOT leave the LN, they cannot exit the node for several hours until ______ is re-expressed and the cell can exit the LN by mechanism of chemotaxis

S1PR1

Ag-activated T cells continue to express low levels of S1PR1 and stay in the LN for several days, S1PR1 is re-expressed on Ag-activated T cells after several days and activated and differentiated effector T cells then

sense the S1P gradient and exit the node

activated effector T cells home to

sites of infection in peripheral tissues

cell migration into tissue is mediated by

E-selectin, P-selectin, and activated integrins (by chemokines)

chemokine CCL4 original name major function

MIP-1beta T cell, DC, monocyte, and NK recruitment; HIV coreceptor

chemokine CXCL10 original name major function

IP-10 effector T cell recruitment

immature naive B cells leave the bone marrow through the blood and enter the _______ and migrate to the

red pulp of the spleen periphery of the white pulp

maturation of B cells occurs in the

white pulp of the spleen

mature naive B cells reenter the circulation (after maturing in the white pulp of the spleen) and home to

LNs and mucosal lymphoid tissues

mature naive B cells use the same basic mechanisms mediated by L-selectin for homing of mature naive B cells from the blood into LNs including rolling mediated by

interactions with L-selectin ligands expressed on HEVs, chemokine dependent activation of integrins, and stable arrest just as naive T cells

chemokine CXCL12 original name major function

SDF-1alphabeta homing naive B cells to LNs; activation of integrins requires CXCL12 expressed on HEV and their chemokine receptors

chemokine CXCL13 original name major function

BCA-1 B cell migration into follicles; T follicular helper cell migration into follicles

in follicles, if B cells encounter their Ag, they become

activated