excellent review article : ley et al., nature immunology reviews, 7:678, 2007

Excellent review article : Ley et al., Nature Immunology Reviews, 7:678, 2007Video Acknowledgments to Dr. Tim Springer, Harvard University

Homing of naïve/effector/memory cells

Recruitment of phagocytic cells

Leukocyte/Lymphocyte Trafficking

Functions in Immune Response:

Adhesion Molecules

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 PictureEndothelial Cells

Blood Flow -->

PMN

Rolling Activation

Firm Adhesion

Diapedesis

ADHESION MOLECULE FAMILIES(and related proteins)

1.

2.

3.

4.

Selectins - Family of C-type Lectins

Integrins - Family of HeterodimericReceptors b2-integrins

Cell Adhesion Molecules (CAMs) - Composed of Ig Domains

Signaling Molecules (Receptors/Ligands) - Chemoattractant and Chemokine Receptors

Physical Factors InfluencingLymphocyte/Leukocyte Migration

1.

2.

3.

Blood Flow

Physical Barriers

Ability to Detect Infection

Step 1: Rolling

Selectins & CHO LigandsStep 1: Rolling

***

Endothelium

Leukocyte

P-Selectin

E-Selectin

L-Selectin

Sialyl Lewis X and others

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

Chemotactic Receptors & Ligands

Step 2: Activation

FMLP

IL-1

C5aTNF-a

Infection

1. Activates both cell types – endothelial and leukocyte2. Causes “inside-out signaling3. Gradient-dependent migration of leukocytes

b2-integrins and Inflammatory Activators

NH2

COOH

FMLPPAF

IL-8

C5a

a bG protein Complex

Inside-Out Signaling

Cell AdhesionMolecules - CAMS

Endothelium

S S S SS SS SS SS SS S

S S S SS SS SS SS S

S S S SS SS SS SS SICAM-1

ICAM-2

VCAM

PECAM

Step 3: Firm Adhesion

Infection Inflammatory Mediators

InflammatoryMediators

LAD I - Leukocyte Adhesion Deficiency Type 1Missing functional CD18 : no expression of CD11a-d

PECAM:PECAM Integrin:ICAM

JAM-1:Integrin JAM-1:JAM-1

Step 4: Diapedesis

Endothelial Cells

Blood Flow

Leukocyte

Rolling

Selectin-mediated

1 Activation

Cytokine-mediated

2

FirmAdhesion

Migration

Integrin-mediated

34

Naïve Lymphocyte Homing in Lymph Nodes

L-Selectin

SSSSSSSSSS

LFA-1

ICAM-1PNAd

CCR7

CCL19

Rolling

Activation Firm Adhesion