Leukocyte/Lymphocyte Trafficking
Adhesion Molecules
Functions in Immune Response:
Homing of naïve/effector/memory cells
Recruitment of phagocytic cells
Excellent review article : Ley et al., Nature Immunology Reviews, 7:678, 2007
Video Acknowledgments to Dr. Tim Springer, Harvard University
Leukocyte Recirculation
IMMUNOSURVEILLANCE
Critical for Effective Immune Responses
Constant Process – required for rapidly
controlling infections
Leukocyte adhesion deficiencies –
highlight the role of certain adhesion
molecules in this process
The Big Picture
Endothelial Cells
Rolling
Activation
Blood Flow -->
Firm Adhesion
PMN
Diapedesis
ADHESION MOLECULE FAMILIES
(and related proteins)
1. Selectins - Family of C-type Lectins
2. Integrins - Family of Heterodimeric
Receptors b2-integrins
3. Cell Adhesion Molecules (CAMs) Composed of Ig Domains
4. Signaling Molecules (Receptors/Ligands) Chemoattractant and Chemokine Receptors
Physical Factors Influencing
Lymphocyte/Leukocyte Migration
1. Blood Flow
2. Physical Barriers
3. Ability to Detect Infection
Step 1: Rolling
Step 1: Rolling
Selectins & CHO Ligands
P-Selectin
L
e
u
k
o
c
y
t
e
L-Selectin
E-Selectin
Sialyl Lewis X and others
E
n
d
o
t
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m
Intravital Microscopy. The mouse mesentery preparation.
The following in vivo microscopy is of postcapillary venules
from a different type of preparation, hamster cheek pouch
Timothy A. Springer, Harvard Medical School
Timothy A. Springer, Harvard Medical School
IMMUNOSURVEILLANCE
Incomplete glycosylation of
sLewx: no binding to selectins
LAD II - Leukocyte Adhesion
Deficiency Type 2
Step 2: Activation
Step 2: Activation
Chemotactic Receptors
& Ligands
FMLP
IL-1
Infection
TNF-a
C5a
1. Activates both cell types – endothelial and leukocyte
2. Causes “inside-out signaling
3. Gradient-dependent migration of leukocytes
b2-integrins and Inflammatory Activators
C5a
PAF
FMLP
IL-8
NH2
COOH
a
b
G protein Complex
Inside-Out Signaling
Cell Adhesion
Molecules - CAMS
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
PECAM
VCAM
S
S
S
S
S
S
ICAM-2
ICAM-1
Endothelium
Step 3: Firm
Adhesion
Infection
Inflammatory Mediators
Inflammatory
Mediators
LAD I - Leukocyte Adhesion
Deficiency Type 1
Missing functional CD18 : no
expression of CD11a-d
Step 4: Diapedesis
PECAM:PECAM
Integrin:ICAM
JAM-1:Integrin
JAM-1:JAM-1
Endothelial Cells
1
Rolling
2
Blood Flow
Activation
Leukocyte
Selectin-mediated
3 Firm
Adhesion
4
Migration
Integrin-mediated
Cytokine-mediated
Naïve Lymphocyte Homing in Lymph Nodes
Rolling
Activation
Firm Adhesion
LFA-1
CCR7
L-Selectin
PNAd
CCL19
S
S
S
S
S
S
S
S
S
S
ICAM-1