Lecture 3: Leukocyte Circulating and Migration into Tissue Flashcards
Migration/recruitment definition
General process of leukocyte movement from blood into tissues
Recirculation
Ability of lymphocytes to repeatedly ‘home’ to SECONDARY lymphoid organs, reside there transiently, and return to the blood
Leukocyte homing
Cell migration out of the blood and into PERIPHERAL TISSUES, or to a site of infection/injury
Major part of process of inflammation
Recruitment of leukocytes and plasma proteins to sites of infection/injury
Inflammation triggered by
Recognition of microbes and dead tissues
Steps of adhesion events
Tethering
Rolling
Adhesion and stop
Transmigration into tissue
Tethering
Occurs through transient interaction of selectins and integrins with their ligands
Rolling
Allows chemokine receptors on leukocytes to bind chemokines expressed on endothelium
Initiated by P-selectin and their ligands
What triggers leukocyte adhesion to endothelium
Receptors signal and activate integrins on leukocytes which interact with ligands on endothelium
Trasmigration
After adhesion, leukocytes transmigrate into extravascular space and migrate down chemokine gradients
What causes expression of adhesion molecules on endothelial cells
Endothelial cells are activated at sites of infection/injury by cytokines secreted from resident immune cells
Consequence of expression of adhesion molecules on endothelial cells
Increased adhesion of myeloid leukocytes and Ag-activated and memory leukocytes, NOT naive luekocytes
T or F: Homing involves molecules on the surfaces of both the leukocytes and endothelial cells
True.
Leukocytes- homing receptors and chemokine receptors
Endothelial cells- chemokines
What are Addressins
A set of adhesion molecules on the surface of HEVs
Selectin affinity is high or low with their ligands
Selectins have low affinity interaction with their ligands
Activated endothelial cells express what selectins
P-selectin and E-selectin
E-selectin expressed on
Expressed on endothelial cells activated by cytokines (TNF, IL-1) within 1-2 hours
Expression of ligands for P selectin and E selectin
Ligands are constitutively expressed
L-selectin expressed on
Expressed on leukocytes/lymphocytes.
Importance of L-selectin
Used by Naive T and B lymphocytes for homing into lymph nodes by interacting with HEVs
Further stabilizes rolling
L-selectin ligand expressed on HEV is called
Peripheral node addressins (PNAds)
P-selectin expressed on
Endothelial cells activated by histamine/thrombin or TNF or IL-1
P-selectin and E- selectin ligand
Sialyl Lewis X
Integrin affinity with ligand
High affinity to ligand
All leukocytes express
Lymphocyte function associated antigen I
LFA-1
LFA-1 ligand name and where its expressed
ICAM-1 on cytokine-activated endothelial cells
VLA-4 expressed where and binds to what
Expressed on leukocytes, binds to VCAM-1 on activated endothelial cells
alpha(4)beta(7)integrin expressed where binds what
Expressed on leukocytes, binds to VCAM-1 and MadCAM on endothelial cells
Mac-1 expressed where binds what
Neutrophils/monocytes/Dendritic cells
ICAM-1, ICAM-2
What activates integrins and what is the result
What type of signaling is this
Chemokines binding to chemokine receptors, causing conformation change in integrin
Result is increase in integrin affinity to ligand
Inside-out signaling
Family/size of chemokine
Large family of cytokines 8-10kD
Chemokine function
Stimulate leukocyte movement and regulate migration of leukocytes from blood to tissues
C vs Beta Vs Alpha vs CX3C chemokines
C- single cysteine
Beta- two cysteines
Alpha- two cysteines separated by one AA
CX3C- two cysteines separated by three AAs
What do neutrophils/monocytes enter tissue through
Post-capillary venules, except in parenchymal tissues (liver, lung, kidney) where all blood enters through capillaries
Neutrophils recognize what ligand on endothelial cells
CXCL8 aka IL-8
Monocytes recognize what ligand on endothelial cells
CCL2 aka MCP-1
Leukocyte migration following diapedesis/transmigration
They adopt amoeboid shape
Migrate in polarized fashion along collagen fibers in response to chemotactic gradient
Naive T-cells inter lymph node through
HEVs
Dendritic cells with Ag enter lymph node through
lymphatic vessels
What happens when T-cell recognize Ag in lymph node
They are activated and return to circulation
What is the result of an L-selectin deficient lymphocyte
They are unable to enter peripheral nodes and “see” the antigen
If a lymphocyte does not find an Ag in the lymph node, what happens
Leaves LN via efferent lymphatics and travels downstream
HEVs are present where
ONLY in SECONDARY lymph organs
What chemokines are on the surface of HEVs
CCL19 and CCL21
Naive T-cell S1PR1 expression and result
Naive T-cells have low S1PR1 expression. They cannot exit node for several HOURS until expression increases and they can detect S1P gradient
Activated T-cell S1PR1 expression and result
T-cells that recently entered LN and are activated still have low S1PR1 expression. It takes several days to re-express S1PR1 and allow exit from node.
CD44 importance
Important for mobilization of effector T cells in sites of infection
Can mediate rolling interactions with endothelial cells expressing Hyaluronic acid or E-selectin
Immature Naive B cell migration and maturation
Migrate from bone marrow, through the blood, enter red pulp then migrate to white pulp
After maturing in white pulp, they home to secondary lymph organs
B cells may be activated where
In lymph node follicles
