Lecture 3 Flashcards
the ability of lymphoctres to repeatedly home to secondary lymphoid organs, reside there transiently, and return to the blood
recirculation
the general process of leukocyte movement from blood into tissues
migration or recruitment
the migration of a leukocyte out of the blood and inot a particular tissue, or to a site of an infection or injury
leukocyte homing
the recruitment of leukoycytes and plasma proteins from the blood to sites of infection and tissue injury ina
major part of the porcess of inflammation
What is inflammation triggered by?
recognition of microbes and dead tissue in innate immune response
What delivers the cells and molecules of host defense to the sites where offending agents need to be combated?
inflmmatory response
P-selectin (CD62P)
endothelium activated by histamine or thrombin
P- selectin ligand
Sialyl Lewis X on PSGL-1 and other glycoproteins; neutrophils, monocytes, T cells (effector, memory)
E-selectin (CD62E_ distribution
endothelium activated by cytokins (TNF, IL-1)
E-selectin Ligand
sialyl Lewis X (CLA-1) on glycoproteins; neutrophils, monocytes, T cells (effector, memory)
L-selectin (CD62L) distribution
neutrophils, monocytes, T cells (naive and central memory), B cells (naive
L-slectin (CD62L) ligand
sialyl lewis X/PNAd on GlyCAM-1, CD34, MadCAM-1, others; endothelium HEV
LFA-1(CD11aCD18) districbution
neutrophils, monocytes, T cells (naive, effector, memory), B cells (naive)
LFA-1 ligand
ICAM-1(ICAM
A cascade of adhesive and activation events underlies the trafficking of all?
Subsets of circulation leukocytes
What can circulating leukocytes do?
Tether to and roll on the endothelium through transient interactions of seletins and integrin w their receptors
Rolling allows leukocytes to?
Sample the endothelium for chemokines
What activate integrins and trigger adhesioin to the endothelium
chemokines
What migraete across teh endothelium into the extravascular space?
adherent leukocytes
When leukocytes arive at extrvascular space,
leukocytes can migrate down chemokine gradients toward specific areas
What constatnly ciruclate through the blood, into tissues and often back into the blood again?
immune cells
What are activated by ctyokines secreted by resident Mo and mast cells at sites of infection and tissue injury?
endothelial cells
What is the result of activated cytokines for increased adhesion?
increased adhesiveness of the endothelial cells for ciruclating myeloid leukocytes and Ag activated effector and memory lymphocytes
What require the temporary adhesion of the leukocyte to the endothelial cells of blood vessels?
leukocyte/lymphocyte homing
What does homing involve?
molecules on the surfaces of both the leukocytes(homing receptors and chemokine receptors) and endothelia cells(chemokines)
What comprise a set of several adhesion molecules on the surface of endothelial cells which regulate lymphocyte recirculation via HEV?
addressins
What express P selectin(CD62P) and E selectin (CD62E)
endothelial cells
What is synthesized and expressed on the endothelial cell surface within 1 to 2 hours in response to the cytokines IL1 and TNF?
E selectin
What is produced by tissue macrophages in response to infections?
IL1 and TNF
What are the ligans for E selectins and P selectins?
complex sialylated carbohydrates
What is ONLY expressed on leukocytes adn lymphocytes but not on endothelial cells?
L selectins(CD62L)
What is L selection expression activated by?
IL1 and TNF at sites of inflammation
What are L selectins important for?
naive T and B lymphocytes for homing into LNs by interacting with high endothelial venules (HEV)
What are L selectin ligands expressed on HEV called??
peripheral node addressins (PNAd)
LFA-1(CD11aCD18) distribution
neutrophils, monocytes, T cells(naive, effector, memory) B cells (naive)
Ligand for LFA-1(CD11aCD1)
ICAM-1(CD54), ICAM-2(CD102); endothelium(cytokine-induced)
Mac-1(CD11bCD18) distribution
neutrophils, monocytes, dendritic cells
Mac-1(CD11bCD18) ligand
ICAM-1(CD54), ICAM-2(CD102); endothelium(cytokine-induced)
VLA-4(CD49aCD29) distribution
monocytes, T cells(naive, effector, membory)
Ligand for VLA-4(CD49aCD29)
VCAM-1(CD106); endothelium (cytokine-induced)
Distribution for alpha4beta7(CD49dCD29)
monocytes, T cells(gut homing, naive, effector, memory), B cells(gut homing)
Ligand for alpha4beta7
VCAM-1 MadCAM1; endothelium in gut and gut associated lymphoid tissues
What are integrins?
hetrodimeric cell surfac proteins
-composed of two noncovalently linked polypeptide chains
What doe integrins do?
mediate adhesion of cells to other cells or to extracellular matrix
How do integrins mediate adhesion?
vaious specific ligands
What cause integrate signals?
extracellular ligands with cytoskeleton dependent motility, shape change, and phagocytic responds
How are integrins able to response to intracellular signals?
by rapidly increasing their affinity for their ligands(integrin activation)
Integrin activation that occurs in all leukocyres is in response to?
chemokine binding to chemokine receptors
in T lymphocytes integrin activation occurs>?
when Ag binds to TCRs
What is integrin activation mediated by?
chemokine-induced conformational changes in teh extracellular domains of the integrins that lead to increased affinity
Why type of chemokine signaling leads to increased affinity?
inside-out signaling, which is involved in intgrin activation
The inegrins on blood leukocytes are nomrally
in a low affinity state
When rolling of leukocytes occurs, chemokines displayed on the endothelial surface?
bind chemokine receptors on the leukocytes
What happens when chemokine receptor signalling occurs?
activates the leukocyte integrins, increasing hteir affinity for their ligands on the endothelial cells
What are chemokines?
A large family of structurally homlogous cytokines of 8-10 kD that contain two internal disulfide loops
What do chemokines stimulate?
leukocyte movment and regulate the migration of leukocytes from the blood to tissues
How many human chemokines?
50, classified inot four families on number and location of N termal cystein residues
the two defining cystein residues are adjacent
CC or Beta chemokines
these residues are spearatied by one amino acid
CXC or alpha chemokines
a single cysteine
C chemokines
two cysteines are separated by three amino acids
CX3C chemokines
CCL1, I-309
CCR8
-monocyte recruitment and endothelial cell migration
CCL2, MCP-1
CCR2
-mixed leukocyte recruitment
CCL2, MIP-1alpha
CCR1, CCR5
-mixed leukocyte recruitment
CCL4, MIP-1beta
CCR5
-T cell, dendritic cell, monocyte, and NK recuirtment; HIVE coreceptor
CCL5, RANTES
CCR1, CCR3, CCR5
-mixed leukocyte recruitment
CCL11, Eotaxin
CCR3
-Eosinophil, basophil, and TH2 recruitment
CCL19, MIP-3beta
CCR7
T cell and dendritic cell migration into parafollicular zones of lymph nodes
CCL20, MIP-3alpha
CCR6
-Th17 recruitmetn, DC positioning in tissue
CCL21 SLC
CCR7
-T cell and dendritic cell migration into parafollicular zones of lymph nodes
CCL22, MDC
CCR4
-NK cell, T cell recruitment
CXCL1, GROalpha
CXCR2
-neutrophil recruitment
CXCL5, ENA-78
CXCR2
-neutrophil
CXCL8, IL-8
CXCR1, CXCR-2
Neutrophil recruitment
CXCL10, IP-10
CXCR3, CXCR3B
efector T cell recruitment
CXCL11, I-TAC
CXCR3, CXCR7
-effector T cell recruitment
CXCL12, SDF-1alpha beta
CXCR4
-mixed leukocyte recruitment; HIV coreceptor
CXCL13, BCA-1
CXCR5
-B cell migration into follicles; T follicular helper cell migration inot follicles
CXCL14 BRAK
monocyte and dendritic cell migration
XCL1, lymphotactin
XCR1
-T cell and NK cell recruitment
CX3CL1, Fractalkine
CX3CR1
-T cell, NK cell, and monocyte recruitment; CTL and NK cell activation
Neutrophils and monoctes circulating in the blood,
are ready to be recruited into tissue sites of infection or injury without activation
How do neutrohpils and monocyrtes enter tissue?
through post-capillary venules except parenchymal tissues(liver, lungs, kidney) where all blood cells enter through capillaries
What do myeloid leukocytes eliminate?
infectious pathogens, clear dead tissues and repair damage
What controls transmigration of monocytes?
CCL2 (MCP-1)
What further stabilizes rolling?
L-selectins binding to ligands on endothelial cells
What initiates rolling on the endothelium?
P selectins and ligands
What can be induced on the surace of endothelial cells by cytokines?
E selectin expression
Activated resident Mo produe?
ctokines TNF and IL-1 that induce the rapid induction of expression of pre formed P selectin on the surface of endothelial cells
What chemokine do endothelial cells present?
CXC-chemokine ligand 8(CXCL8 also called IL-8) that recognizes by receptors on neutrophils
Transmigrasion of monocytes by CCL2 activates?
leukocyte integrins and results in more stable leukocyte adhesion
Once leukocyte have completed trans-endothelial migration
they interact w chemokines in the underlying basement membrane
What do cell do following diapedesis?
adopt an amoeboid shape
Where are chmotactic receptors located?
the leading edge
once leukocytes have completed trans endothelial migrations,
they interact w chemokines in the underlying basement membrane
How do neutrophils migrate?
In a polarized fashion along collagen fibrils in response to a chemotactic gradient toward the site of infection/inflammation
The mechanisms of recuriment of neutrophils (chomkine IL-8) and monocytes (chemokine MCP) is identical except?
the difference in chemokines involved
preferentially leave the blood and enter peripheral tissues through venules at sites of inflammation
effector and memory T cells
Migration and recirculation of naive T cells
- preferntially leave the blood and enter lymph nodes across the HEV
- dendritic cells bearing Ag enter the lymph nodes through lymphatic vessels
- If the T cells recognize Ag, they are activated, and they return into the arterial ciruculation
L selectin is expressed by?>
T and B lymphocytes
How do naive lymphocytes enter the LN?
through the HEV
Whare are L selectin ligands expressed on HEV called?
peripheral node addressins (PNAd)
Without L selectins lymphocytes are unable to?
enter peripheral nodes and see the Ag
the naive lymphocytes enter the LN through?
an artery, leave the circuitaiton by moving across the wall of the HEV
What are B and T cells drawn to different zones of the LN by?
Chemokines that are produced in these areas
How do Ag-loaded DCs enter the LN?
through afferent lymphatic vessels come from the sites of Ag entry
Where doe DCs migrate in teh LN?
the T cell rich aresa
Nave T lyphocytes home to LN as a result of?
L selectin binding to peripheral lymph node addressin(PNAd) on HEV
What are present only in secondary lymphoid organs?
HEV
What chemokines are displayed on the surface of the HEV?
CCL19 and CCL 21
Chemokines binding to CCR7 activate?
integrins
Naive T cells have low levels of…. bc the receptor is internalized after binding S1P in the blood
S1PR1
Naive T cells that have recently entered a LN
cannot sense S1p concentration gradient btw the T cell zone of the node and the lymph
What can the naive T cell exit the cell?
S1PR1 is re expressed and the cell exit the LN
What have low levels of S1PR1 and the celsl stay in teh LN?
Ag activated T cells
after serval days S1PR1 will be re expressed and … then sense the S1P gradient and exit the node
effector T cells
What home to sites of infection in peripheral tissues?
activated effector T cells
What is cell migration into tissue mediated by?
E selectin and P selectin, integrins, and chmokine(CXCL10) that are produced at sties of infection
What is important for the mobilization of effector T celsl in sites of infection and inflammation?
CD44
At sites of infection and inflammation, endothelial cells secrete?
chemokines and epress E and P selectin and hydronic acid
What can mediate rolling interation?
CD44, with vascular endothelial cellst hat express HA, its natural ligand, or even E selectin
Chemokine signaling via GPCRs results in increased?
integrin affinit, such as VLA-4 which enhances adhasivnbeness(inside out signaling)
Engagement of CD44 and HA may also trigger?
CPCR-dependent inside out upregulaitoin of VLA4VCAM bindign
Naive B cells use the same basic mechanisms as naive T cells to home to secondary lymphoid tissues
throughout the whole body
What leave the bone marrow through the blood, enter the red pulp of the spleen, and migrate to the periphery of the white pulp??
immature B cells
A B cells mature further, they express?
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 for mature naive B cells they?
reenter the circulation and home to lymph nodes and mucosal lymphoid tissues
In the follicles B cells may encounter…. and becomes…
Ag, activated
In the stroma, B cells migrate into?
follicles dirven by CXCL13 recognized by CXCR5 expressed by naive B cells
What does the homing proecess require? Chemokines?
CXCL12 and CCL19/CCL21 on HEV and their chemokine receptors CXCR4 and CCR7 on naive B cells
What does homing of mature naive Be cells from the blood into LNs involve?
rolling interactions on HEVs, chemokine activation of integrins, and stable arrest, as described earlier for naive T cells
