Leukocyte Circulation and Migration into Tissue Flashcards
migration or recruitment is the general process of leukocytes
movement from blood into tissues
recirculation is the ability of lymphocytes to repeatedly:
- home to secondary lymphoid organs
- reside in secondary lymphoid organs transiently
- return to the blood
leukocyte homing is
cell migration out of the blood and into peripheral tissues. mostly occurs in response to an infection or tissue injury
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
inflammation is triggered by
recognition of microbes and dead/injured tissues in innate immune responses and is refined and prolonged during adaptive immune responses
neutrophils and monocytes arise in the
bone marrow and circulate in the blood
neutrophils and monocytes are ready to be recruited into tissues sites of infection and injury with or without activation
without activation
neutrophils and monocytes enter the tissue through _____ except parenchymal tissues (liver, lungs, kidneys) where all blood cells enter through _____
post-capillary venules
capillaries
functions of myeloid leukocytes
eliminate infectious pathogens
clear dead tissues
repair the damage
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
once leukocytes have completed trans-endothelial migration, they
interact with chemokines in the underlying basement membrane
following diapedesis, cells adopt _____ shape
an amoeboid
transmigration of leukocyte:
capture and rolling of cells involves
selectins
transmigration of leukocytes:
activation (rolling -> adhesion) involves
chemokines
transmigration of leukocytes:
firm adhesion involves
adhesion molecules
after diapedesis, leukocytes migrates in a polarized fashion along
collagen fibrils in response to a chemotactic gradient toward the site of infection/inflammation
chemotactic receptors are located where on the migrating leukocyte
on the leading edge
endothelial cells in _____ tissues do not express adhesion molecules on their surfaces facing the blood
healthy
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
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)
tissue recruitment of immune cells:
leukocyte/lymphocyte homing/recruitment requires the temporary
adhesion of the leukocyte/lymphocyte to the endothelial cells of blood vessels
homing involves molecules on the surfaces of both the _____ and _____
leukocyte/lymphocyte (homing receptors and chemokine receptors)
endothelial cells (chemokines)
addressins comprise a set of adhesion molecules expressed only on the surface of
high endothelial venules (HEV)
selectins provide _____ interactions with their ligands
low affinity
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
30
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
30
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
